Biaryl-propionic acid derivatives and their use as pharmaceuticals

ABSTRACT

The present invention relates to compounds of the formula I, 
                         
wherein X, R, R1, R2, D, E1, E2, E3, E4, G1, G2, G3 and G4 have the meanings indicated in the claims, which are valuable pharmaceutical active compounds. They are inhibitors of the protease cathepsin A, and are useful for the treatment of diseases such as atherosclerosis, heart failure, renal diseases, liver diseases or inflammatory diseases, for example. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use and pharmaceutical compositions comprising them.

This application claims the benefit of European Application No.EP13305402.3, filed Mar. 28, 2013, the disclosure of which is hereinincorporated by reference in its entirety.

The present invention relates to compounds of the formula I,

wherein X, R, R1, R2, D, E₁, E₂, E₃, E₄, G₁, G₂, G₃ and G₄ have themeanings indicated below, which are valuable pharmaceutical activecompounds. They are inhibitors of the protease cathepsin A, and areuseful for the treatment of diseases such as atherosclerosis, heartfailure, renal diseases, liver diseases or inflammatory diseases, forexample. The invention furthermore relates to processes for thepreparation of the compounds of the formula I, their use andpharmaceutical compositions comprising them.

Cathepsin A (EC=3.4.16.5; gene symbol CTSA) is a protease also known aslysosomal carboxypeptidase A or protective protein. It belongs to afamily of serine carboxypeptidases which contains only two othermammalian representatives, retinoid-inducible serine carboxypeptidaseand vitellogenic carboxypeptidase-like protein. Within the cellcathepsin A resides in lysosomes where it forms a high molecular weightcomplex with beta-galactosidase and neuraminidase. The interaction ofcathepsin A with these glycosidases is essential for their correctrouting to the lysosome and protects them from intralysosomalproteolysis. A deficiency of cathepsin A resulting from variousmutations in the ctsa gene leads to a secondary deficiency ofbeta-galactosidase and neuraminidase that is manifest as the autosomalrecessive lysosomal storage disorder galactosialidosis (cf. A. d'Azzo etal., in “The Metabolic and Molecular Bases of Inherited Disease”, vol. 2(1995), 2835-2837). The majority of identified mutations in ctsa aremissense mutations affecting the folding or the stability of theprotein. None of them was shown to occur in the active site of theenzyme (G. Rudenko et al., Proc. Natl. Acad. Sci. USA 95 (1998),621-625). Accordingly, the lysosomal storage disorder can be correctedwith catalytically inactive cathepsin A mutants (N. J. Galjart et al.,J. Biol. Chem. 266 (1991), 14754-14762). The structural function ofcathepsin A is therefore separable from its catalytic activity. This isalso underscored by the observation that in contrast to mice deficientin the ctsa gene, mice carrying a catalytically inactivating mutation inthe ctsa gene do not develop signs of the human diseasegalactosialidosis (R. J. Rottier et al., Hum. Mol. Genet. 7 (1998),1787-1794; V. Seyrantepe et al., Circulation 117 (2008), 1973-1981).

Cathepsin A displays carboxypeptidase activity at acidic pH anddeamidase and esterase activities at neutral pH against variousnaturally occurring bioactive peptides. In vitro studies have indicatedthat cathepsin A converts angiotensin I to angiotensin 1-9 andbradykinin to bradykinin 1-8, which is the ligand for the bradykinin B1receptor. It hydrolyzes endothelin-1, neurokinin and oxytocin, anddeamidates substance P (cf. M. Hiraiwa, Cell. Mol. Life. Sci. 56 (1999),894-907). High cathepsin A activity has been detected in urine,suggesting that it is responsible for tubular bradykinin degradation (M.Saito et al., Int. J. Tiss. Reac. 17 (1995), 181-190). However, theenzyme can also be released from platelets and lymphocytes and isexpressed in antigen-presenting cells where it might be involved inantigen processing (W. L. Hanna et al., J. Immunol. 153 (1994),4663-4672; H. Ostrowska, Thromb. Res. 86 (1997), 393-404; M. Reich etal., Immunol. Lett. (online Nov. 30, 2009)). Immunohistochemistry ofhuman organs revealed prominent expression in renal tubular cells,bronchial epithelial cells, Leydig's cells of the testis and largeneurons of the brain (0. Sohma et al., Pediatr. Neurol. 20 (1999),210-214). It is upregulated during differentiation of monocytes tomacrophages (N. M. Stamatos et al., FEBS J. 272 (2005), 2545-2556).Apart from structural and enzymatic functions, cathepsin A has beenshown to associate with neuraminidase and an alternatively splicedbeta-galactosidase to form the cell-surface laminin and elastin receptorcomplex expressed on fibroblasts, smooth muscle cells, chondroblasts,leukocytes and certain cancer cell types (A. Hinek, Biol. Chem. 377(1996), 471-480).

The importance of cathepsin A for the regulation of local bradykininlevels has been demonstrated in animal models of hypertension.Pharmacological inhibition of cathepsin A activity increased renalbradykinin levels and prevented the development of salt-inducedhypertension (H. Ito et al., Br. J. Pharmacol. 126 (1999), 613-620).This could also be achieved by antisense oligonucleotides suppressingthe expression of cathepsin A (I. Hajashi et al., Br. J. Pharmacol. 131(2000), 820-826). Besides in hypertension, beneficial effects ofbradykinin have been demonstrated in various further cardiovasculardiseases and other diseases (cf. J. Chao et al., Biol. Chem. 387 (2006),665-75; P. Madeddu et al., Nat. Clin. Pract. Nephrol. 3 (2007),208-221). Key indications of cathepsin A inhibitors therefore includeatherosclerosis, heart failure, cardiac infarction, cardiac hypertrophy,vascular hypertrophy, left ventricular dysfunction, in particular leftventricular dysfunction after myocardial infarction, renal diseases suchas renal fibrosis, renal failure and kidney insufficiency; liverdiseases such as liver fibrosis and liver cirrhosis, diabetescomplications such as nephropathy, as well as organ protection of organssuch as the heart and the kidney.

As indicated above, cathepsin A inhibitors can prevent the generation ofthe bradykinin B1 receptor ligand bradykinin 1-8 (M. Saito et al., Int.J. Tiss. Reac. 17 (1995), 181-190). This offers the opportunity to usecathepsin A inhibitors for the treatment of pain, in particularneuropathic pain, and inflammation, as has been shown for bradykinin B1receptor antagonists (cf. F. Marceau et al., Nat. Rev. Drug Discov. 3(2004), 845-852). Cathepsin A inhibitors can further be used asanti-platelet agents as has been demonstrated for the cathepsin Ainhibitor ebelactone B, a propiolactone derivative, which suppressesplatelet aggregation in hypertensive animals (H. Ostrowska et al., J.Cardiovasc. Pharmacol. 45 (2005), 348-353).

Further, like other serine proteases such as prostasin, elastase ormatriptase, cathepsin A can stimulate the amiloride-sensitive epithelialsodium channel (ENaC) and is thereby involved in the regulation of fluidvolumes across epithelial membranes (cf. C. Planes et al., Curr. Top.Dev. Biol. 78 (2007), 23-46). Thus, respiratory diseases can beameliorated by the use of cathepsin A inhibitors, such as cysticfibrosis, chronic bronchitis, chronic obstructive pulmonary disease,asthma, respiratory tract infections and lung carcinoma. Cathepsin Amodulation in the kidney could be used to promote diuresis and therebyinduce a hypotensive effect. Also beneficial effects of Cathepsin Ainhibitors on atrial fibrillation are reported in J. Med. Chem. 2012,55, no. 17, 7636-7649.

Besides for the above-mentioned compound ebelactone B, an inhibitoryeffect on cathepsin A has been found for certain dipeptidicphenylalanine derivatives which are described in JP 2005/145839. Also inWO2011/092187, WO2012/101197, WO2012/101199, PCT/EP2012/064628,PCT/EP2012/064629, PCT/EP2012/072538, PCT/EP2012/072539 compounds withinhibitory activity on Cathepsin A are disclosed. There is a need forfurther compounds which inhibit cathepsin A and offer an opportunity forthe treatment of the mentioned diseases and further diseases in whichcathepsin A plays a role. The present invention satisfies this need byproviding the oxygen-substituted 3-heteroaroylamino-propionic acidderivatives of the formula I defined below.

Certain compounds in which a 3-heteroaroylamino-propionic acid moietycan be present, have already been described. For example, in WO2006/076202 amine derivatives, which modulate the activity of steroidnuclear receptors, are described which carry on the nitrogen atom of theamine function a heteroaroyl group and a further group which is definedvery broadly. In US 2004/0072802 broadly-defined beta-amino acidderivatives are described which carry an acyl group on the beta-aminogroup and are inhibitors of matrix metalloproteases and/or tumornecrosis factor. In WO 2009/080226 and WO 2009/080227, which relate toantagonists of the platelet ADP receptor P2Y12 and inhibit plateletaggregation, pyrazoloylamino-substituted carboxylic acid derivatives aredescribed which, however, additionally carry a carboxylic acidderivative group on the carbon atom carrying the pyrazoloylamino group.Other pyrazoloylamino-substituted compounds, in which the nitrogen atomof the amino group is connected to a ring system and which areinhibitors of the blood clotting enzymes factor Xa and/or factor Vila,are described in WO 2004/056815.

A subject of the present invention is a compound of the formula I, inany of its stereoisomeric forms or a mixture of stereoisomeric forms inany ratio, or a physiologically acceptable salt thereof, or aphysiologically acceptable solvate of any of them,

wherein the meanings are:X is S or O;D is N or —C(R3)=;R is H, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl;R1 is H, F, Cl, CF₃, CN, CO—H, CO—(C₁-C₆)-alkyl, CO—NR20R21; wherein R20andR21 are independently from each other H or (C₁-C₆)-alkyl;R3 is H, methyl or ethyl;R2 is Hydrogen or (C₁-C₆-)-alkyl;E₁ is N or —C(R4)=;E₂ is N or —C(R5)=;E₃ is N or —C(R6)=;E₄ is N or —C(R7)=; wherein none or one of E₁, E₂, E₃ or E₄ is N;R4 is H or O—(C₁-C₆)-alkyl;R5 is H F, Cl, CF₃, (C₁-C₆)-alkyl, (C₁-C₆)-cycloalkyl;R6 is H;R7 is H;G₁ is N or —C(R8)=;G₂ is N or —C(R9)=;G₃ is N or —C(R10)=;G₄ is N or —C(R11)=; wherein none or one of G₁, G₂, G₃ or G₄ is N; or G₃and G₄ are —C(R10)= and —C(R11)=, wherein R10 and R11 form a 4 to 7membered saturated carbocycle- or heterocycle with one or two oxygenatoms; which is optionally mono- or disubstituted by (C₁-C₃)-alkyl;R8 is H, F, Cl, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃ or OCF₃;R9 is H, F, Cl, OH, O—(C₁-C₆)-alkyl, CH₂OH, CO—NH₂, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl,CF₃ or OCF₃;R10 is H, F, Cl, OH, (C₁-C₆)-alkyl, CH₂OH, CO—O—(C₁-C₆)-alkyl,SO₂—(C₁-C₆)-alkyl, CN, O—(C₁-C₆)-alkyl, CF₃ or OCF₃;R11 is H, F, Cl, OH, O—(C₁-C₆)-alkyl, CH₂OH, CO—(C₁-C₆)-alkyl,CO—N(R20R21), CO—O—(C₁-C₆)-alkyl, CN, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl orOCF₃; wherein R20 and R21 are independently from each other H or(C₁-C₃)-alkyl or form together with the nitrogen to which they areattached a 5 or 6 membered saturated ring.

In terms of formulae resulting from formula I by incorporation ofmeanings of D, X, E₁, E₂, E₃, and E₄, or G₁, G₂, G₃ and G, in oneembodiment of the invention a compound of the formula I is a compound ofany one or more of formulae I-1 to I-20, for example a compound offormula I-1, or a compound of formula I-2, or a compound of formula I-3,or a compound of formula I-4, or a compound of formula I-5, or acompound of formula I-6, or a compound of formula I-7, or a compound offormula I-8, or a compound of formula I-9 or formula I-10, or a compoundof formula I-11 or formula I-12, or a compound of formula I-13 orformula I-14 or formula I-15, or formula I-16, or formula I-17, orformula I-18, or formula I-19, or formula I-20, in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a physiologically acceptable salt thereof, or a physiologicallyacceptable solvate of any of them, wherein in the compounds of formulaeI-1 to I-20 the groups D, R, R1, R2, R4, R5, R6, R7, R8, R9, R10, R11,E₁, E₂, E₃, E₄, G₁, G₂, G₃ and G₄, are defined as in the compounds offormula I in general or in any embodiment specified above or below.

Another embodiment of the invention are compounds of formula I-1, I-2,I-3, I-4, I-5, I-11, I-12, I-13, I-14 or I-15, the groups D, R, R1, R2,R4, R5, R6, R7, R8, R9, R10, R11, E₁, E₂, E₃, E₄, defined as in thecompounds of formula I in general or in any embodiment specified aboveor below,

wherein

G₁ is —C(R8)=;

G₂ is —C(R9)=;

G₃ is —C(R10)=;

G₄-C(R11)=.

Another embodiment of the invention are compounds of formula I-1, I-2,I-3, I-4, I-5, I-11, I-12, I-13, I-14 or I-15, the groups D, R, R1, R2,R4, R5, R6, R7, R8, R9, R10, R11, E₁, E₂, E₃, E₄, defined as in thecompounds of formula I in general or in any embodiment specified aboveor below, wherein

G₁ is N;

G₂ is —C(R9)=;

G₃ is —C(R10)=;

G₄-C(R11)=.

Another embodiment of the invention are compounds of formula I-1, I-2,I-3, I-4, I-5, I-11, I-12, I-13, I-14 or I-15, the groups D, R, R1, R2,R4, R5, R6, R7, R8, R9, R10, R11, E₁, E₂, E₃, E₄, defined as in thecompounds of formula I in general or in any embodiment specified aboveor below, wherein

G₁ is —C(R8)=;

G₂ is N;

G₃ is —C(R10)=;

G₄ is —C(R11)=.

Another embodiment of the invention are compounds of formula I-1, I-2,I-3, I-4, I-5, I-11, I-12, I-13, I-14 or I-15, the groups D, R, R1, R2,R4, R5, R6, R7, R8, R9, R10, R11, E₁, E₂, E₃, E₄, defined as in thecompounds of formula I in general or in any embodiment specified aboveor below, wherein

G₁ is —C(R8)=;

G₂ is —C(R9)=;

G₃ is N;

G₄-C(R11)=.

Another embodiment of the invention are compounds of formula I-1, I-2,I-3, I-4, I-5, I-11, I-12, I-13, I-14 or I-15, the groups D, R, R1, R2,R4, R5, R6, R7, R8, R9, R10, R11, E₁, E₂, E₃, E₄, defined as in thecompounds of formula I in general or in any embodiment specified aboveor below, wherein

G₁ is —C(R8)=;

G₂ is —C(R9)=;

G₃ is —C(R10)=;

G₄ is N.

Another embodiment of the invention are compounds of formula I-6, I-7,I-8, I-9, I-10, I-16, I-17, I-18, I-19 or I-20, the groups D, R, R1, R2,R4, R5, R6, R7, R8, R9, R10, R11, G₁, G₂, G₃ and G₄, defined as in thecompounds of formula I in general or in any embodiment specified aboveor below, wherein

E₁ is —C(R4)=;

E₂ is —C(R5)=;

E₃ is —C(R6)=;

E₄ is —C(R7)=.

Another embodiment of the invention are compounds of formula I-6, I-7,I-8, I-9, I-10, I-16, I-17, I-18, I-19 or I-20, the groups D, R, R1, R2,R4, R5, R6, R7, R8, R9, R10, R11, G₁, G₂, G₃ and G₄, defined as in thecompounds of formula I in general or in any embodiment specified aboveor below, wherein

E₁ is N;

E₂ is —C(R5)=;

E₃ is —C(R6)=;

E₄ is —C(R7)=.

Another embodiment of the invention are compounds of formula I-6, I-7,I-8, I-9, I-10, I-16, I-17, I-18, I-19 or I-20, the groups D, R, R1, R2,R4, R5, R6, R7, R8, R9, R10, R11, G₁, G₂, G₃ and G₄, defined as in thecompounds of formula I in general or in any embodiment specified aboveor below, wherein

E₁ is —C(R4)=;

E₂ is N;

E₃ is —C(R6)=;

E₄ is —C(R7)=.

Another embodiment of the invention are compounds of formula I-6, I-7,I-8, I-9, I-10, I-16, I-17, I-18, I-19 or I-20, the groups D, R, R1, R2,R4, R5, R6, R7, R8, R9, R10, R11, G₁, G₂, G₃ and G₄, defined as in thecompounds of formula I in general or in any embodiment specified aboveor below, wherein

E₁ or —C(R4)=;

E₂ is —C(R5)=;

E₃ is N;

E₄ is —C(R7)=.

Another embodiment of the invention are compounds of formula I-6, I-7,I-8, I-9, I-10, I-16, I-17, I-18, I-19 or I-20, the groups D, R, R1, R2,R4, R5, R6, R7, R8, R9, R10, R11, G₁, G₂, G₃ and G₄, defined as in thecompounds of formula I in general or in any embodiment specified aboveor below, wherein

E₁ is —C(R4)=;

E₂ is —C(R5)=;

E₃ is —C(R6)=;

E₄ is N.

Another embodiment of the invention are compounds of formula I-1 or I-11

wherein the groups D, R, R1, R2, R4, R5, R6, R7, R8, R9, R10, R11 aredefined as in the compounds of formula I in general or in any embodimentspecified above or below, whereinG₁ is —C(R8)=;G₂ is —C(R9)=;G₃ is —C(R10)=;G₄ is —C(R11)=.

One embodiment of the invention are compounds of formula I wherein

R is Hydrogen, methyl or ethyl.

One embodiment of the invention are compounds of formula I wherein

R1 is H, F, Cl, CF₃, CN, CO—H, CO—(C₁-C₂)-alkyl, CO—NH₂, CO—NHR21,CO—N((C₁-C₂)-alkyl)₂, wherein R21 is H or (C₁-C₂)-alkyl.

One embodiment of the invention are compounds of formula I wherein

R1 is H, F, Cl, CF₃, CN, CO—H, CO-methyl, CO—NH₂, CO—N(CH₃)₂.

One embodiment of the invention are compounds of formula I wherein

R2 is Hydrogen or (C₁-C₆-)-alkyl.

One embodiment of the invention are compounds of formula I wherein

R2 is Hydrogen.

One embodiment of the invention are compounds of formula I wherein

R4 is H or O-methyl.

One embodiment of the invention are compounds of formula I wherein

R5 is H F, Cl, CF₃, (C₁-C₆)-alkyl, cyclopropyl.

One embodiment of the invention are compounds of formula I wherein

R8 is H, F, Cl, methyl, O-methyl, CF₃ or OCF₃.

One embodiment of the invention are compounds of formula I wherein

R8 is H, F, Cl, methyl or O-methyl.

One embodiment of the invention are compounds of formula I wherein

R9 is H, F, Cl, OH, O-propyl, CH₂OH, CO—NH₂, methyl, O-methyl, CF₃ orOCF₃;

One embodiment of the invention are compounds of formula I wherein

R9 is H, F, Cl, OH, O-propyl, CH₂OH, CO—NH₂, methyl, O-methyl.

One embodiment of the invention are compounds of formula I wherein

R10 is H, F, Cl, OH, i-propyl, t-butyl, CH₂OH, CO—O-methyl, SO₂-methyl,CN, methyl, O-methyl, CF₃ or OCF₃.

One embodiment of the invention are compounds of formula I wherein

R10 is H, F, Cl, OH, methyl, i-propyl, t-butyl, CH₂OH, CO—O-methyl,O-methyl.

One embodiment of the invention are compounds of formula I wherein

R11 is H, F, Cl, OH, O-methyl, O-i-propyl, CH₂OH, CO-methyl,CO—N(methyl)₂, CO-pyrrolidin, CO—O-methyl, CN, methyl or OCF₃;

One embodiment of the invention are compounds of formula I wherein

R11 is H, F, Cl, OH, methyl, O-i-propyl, CH₂OH, CO-methyl,CO—N(methyl)₂, CO—O-methyl, O-methyl.

One embodiment of the invention are compounds of formula I wherein

G₃ and G₄ are —C(R10)= and —C(R11)=, wherein R10 and R11 form a 5 or 6membered saturated carbocycle or heterocycle with one or two oxygenatoms; which is optionally mono- or disubstituted by halogen and or(C₁-C₃)-alkyl.

One embodiment of the invention are compounds of formula I wherein

G₁ is —C(R8)=;

G₂ is —C(R9)=;

G₃ is —C(R10)=;

G₄ is —C(R11)=;

wherein R10 and R11 form a 5 or 6 membered saturated carbocycle orheterocycle with one or two oxygen atoms; which is optionally mono- ordisubstituted by (C₁-C₃)-alkyl forming a bycyclic ringstructure selectedfrom

One embodiment of the invention are compounds of formula I wherein

G₁ is —C(R8)=;

G₂ is —C(R9)=;

G₃ is —C(R10)=;

G₄ is —C(R11)=;

wherein R10 and R11 form a 5 membered saturated carbo- or heterocyclewith one or two oxygen atoms which is optionally mono- or disubstitutedby (C₁-C₃)-alkyl forming a bycyclic ringstructure selected from

One embodiment of the invention are compounds of formula I wherein

G₁ is —C(R8)=;

G₂ is —C(R9)=;

G₃ is —C(R10)=;

G₄ is —C(R11)=;

wherein R10 and R11 form a 6 membered saturated carbo- or heterocyclewith one or two oxygen atoms which is optionally mono- or disubstitutedby (C₁-C₃)-alkyl forming a bycyclic ringstructure selected from

Another embodiment of the invention are compounds of formula I wherein

G₁ is —C(R8)=;

G₂ is —C(R9)=;

G₃ and G₄ are —C((methyl)₂)—CH₂—O—;

R8 is H;

R9 is H.

Another embodiment of the invention are compounds of formula I wherein

X is S;

D is —C(R3)=;

R is Hydrogen or methyl or ethyl;

R3 is H, methyl or ethyl.

Another embodiment of the invention are compounds of formula I wherein

X is O;

D is —C(R3)=;

R is Hydrogen or methyl or ethyl;

R3 is H, methyl or ethyl.

Another embodiment of the invention are compounds of formula I wherein

X is O;

D is N;

R is Hydrogen or methyl or ethyl;

R3 is H, methyl or ethyl.

Alkyl groups, i.e. saturated hydrocarbon residues, can be linear(straight-chain) or branched. This also applies if these groups aresubstituted or are part of another group, for example an alkyl-O— group(alkyloxy group, alkoxy group) or an HO-substituted alkyl group(hydroxyalkyl group). Depending on the respective definition, the numberof carbon atoms in an alkyl group can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or10, or 1, 2, 3, 4, 5, 6, 7 or 8, or 1, 2, 3, 4, 5 or 6, or 1, 2, 3 or 4,or 1, 2 or 3, or 1 or 2, or 1, for example. In one embodiment of theinvention, a (C₁-C₁₀-alkyl group present in the compounds of the formulaI is a (C₁-C₈)-alkyl group, in another embodiment a (C₁-C₆)-alkyl group,in another embodiment a (C₁-C₄)-alkyl group, in another embodiment a(C₁-C₃)-alkyl group, in another embodiment a (C₁-C₂)-alkyl group, inanother embodiment a (C₂-C₃)-alkyl group, in another embodiment a methylgroup. In one embodiment of the invention, a (C₁-C₈)-alkyl group presentin any position of the compounds of the formula I is a (C₁-C₆)-alkylgroup, in another embodiment a (C₁-C₄)-alkyl group, in anotherembodiment a (C₁-C₃)-alkyl group, in another embodiment a (C₁-C₂)-alkylgroup, in another embodiment a (C₂-C₃)-alkyl group, in anotherembodiment a methyl group, where any (C₁-C₆)-alkyl group present in thecompounds of the formula I can independently of each other (C₁-C₈)-alkylgroup be a group of any of these embodiments. In one embodiment of theinvention, a (C₁-C₆)-alkyl group present in any position of thecompounds of the formula I is a (C₁-C₄)-alkyl group, in anotherembodiment a (C₁-C₃)-alkyl group, in another embodiment a (C₁-C₂)-alkylgroup, in another embodiment a (C₂-C₃)-alkyl group, in anotherembodiment a methyl group, where any (C₁-C₆)-alkyl group present in thecompounds of the formula I can independently of each other (C₁-C₆)-alkylgroup be a group of any of these embodiments. In one embodiment of theinvention, a (C₁-C₄)-alkyl group present in any position of thecompounds of the formula I is a (C₁-C₃)-alkyl group, in anotherembodiment a (C₁-C₂)-alkyl group, in another embodiment a (C₂-C₃)-alkylgroup, in another embodiment a methyl group, where any (C₁-C₄)-alkylgroup present in the compounds of the formula I can independently ofeach other (C₁-C₄)-alkyl group be a group of any of these embodiments.Examples of alkyl groups are methyl, ethyl, propyl groups includingpropyl (i.e. n-propyl) and isopropyl, butyl groups including butyl (i.e.n-butyl), sec-butyl, isobutyl and tert-butyl, pentyl groups includingpentyl (i.e. n-pentyl), 1-methylbutyl, isopentyl, neopentyl andtert-pentyl, hexyl groups including hexyl (i.e. n-hexyl),3,3-dimethylbutyl and isohexyl, heptyl groups including heptyl (i.e.n-heptyl), octyl groups including octyl (i.e. n-octyl), nonyl groupsincluding nonyl (i.e. n-nonyl), and decyl groups including decyl (i.e.n-decyl). Examples of alkyl-O— groups are methoxy, ethoxy, propoxy (i.e.n-propoxy), isopropoxy, butoxy (i.e. n-butoxy), isobutoxy, tert-butoxy,pentoxy (i.e. n-pentoxy). Examples of alkyl-S(O)_(m)— aremethylsulfanyl-(CH₃—S—), methanesulfinyl-(CH₃—S(O)—), methanesulfonyl(CH₃—S(O)₂—), ethylsulfanyl-(CH₃—CH₂—S—),ethanesulfinyl-(CH₃—CH₂—S(O)—), ethanesulfonyl (CH₃—CH₂—S(O)₂—),1-methylethylsulfanyl-((CH₃)₂CH—S—),1-methylethanesulfinyl-((CH₃)₂CH—S(O)—), 1-methylethanesulfonyl((CH₃)₂CH—S(O)₂—). In one embodiment of the invention the number m ischosen from 0 and 2, wherein all numbers m are independent of each otherand can be identical or different. In another embodiment the number m inany of its occurrences is, independently of its meaning in otheroccurrences, 0. In another embodiment the number m in any of itsoccurrences is, independently of its meaning in other occurrences, 2.

A substituted alkyl group can be substituted in any positions, providedthat the respective compound is sufficiently stable and is suitable as apharmaceutical active compound. The prerequisite that a specific groupand a compound of the formula I are sufficiently stable and suitable asa pharmaceutical active compound, applies in general with respect to thedefinitions of all groups in the compounds of the formula I. In oneembodiment of the invention, an individual carbon atom in any alkylgroup in the compounds of the formula I, as well as in other groups suchas cycloalkyl groups and heterocyclic groups, for example, independentlyof any other carbon atom does not carry more than one substituent whichis bonded via an oxygen atom, nitrogen atom or sulfur atom, such as HO—,(C₁-C₄)-alkyl-O— or (C₁-C₄)-alkyl-S(O)_(m)— substituents, for example.An alkyl group which is optionally substituted by one or more fluorinesubstituents can be unsubstituted, i.e. not carry fluorine substituents,or substituted, for example by one, two, three, four, five, six, seven,eight, nine, ten or eleven fluorine substituents, or by one, two, three,four, five, six or seven fluorine substituents, or by one, two, three,four or five fluorine substituents, or by one, two or three fluorinesubstituents, which can be located in any positions. For example, in afluoro-substituted alkyl group one or more methyl groups can carry threefluorine substituents each and be present as trifluoromethyl groups,and/or one or more methylene groups (CH₂) can carry two fluorinesubstituents each and be present as difluoromethylene groups. Theexplanations with respect to the substitution of a group by fluorinealso apply if the group additionally carries other substituents and/oris part of another group, for example of an alkyl-O— group. Examples offluoro-substituted alkyl groups are trifluoromethyl, 2-fluoroethyl,1-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl,4,4,4-trifluorobutyl and heptafluoroisopropyl. Examples offluoro-substituted alkyl-O— groups are trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy and 3,3,3-trifluoropropoxy.Examples of fluoro-substituted alkyl-S(O)_(m)— groups aretrifluoromethylsulfanyl-(CF₃—S—), trifluoromethanesulfinyl-(CF₃—S(O)—)and trifluoromethanesulfonyl (CF₃—S(O)₂—).

The number of ring carbon atoms in a (C₃-C₇)-cycloalkyl group can be 3,4, 5, 6 or 7. Examples of cycloalkyl are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. As regards the optionalsubstitution of cycloalkyl groups by one or more (C₁-C₄)-alkylsubstituents, they be unsubstituted, i.e. not carry alkyl substituents,or substituted, for example by one, two, three or four, or by one ortwo, identical or different (C₁-C₄)-alkyl substituents, for example bymethyl groups, which substituents can be located in any positions.Examples of such alkyl-substituted cycloalkyl groups are1-methylcyclopropyl, 2,2-dimethylcyclopropyl, 1-methylcyclopentyl,2,3-dimethylcyclopentyl, 1-methylcyclohexyl, 4-methylcyclohexyl,4-isopropylcyclohexyl, 4-tert-butylcyclohexyl and3,3,5,5-tetramethylcyclohexyl. As regards the optional substitution ofcycloalkyl groups by one or more fluorine substituents, they can beunsubstituted, i.e. not carry fluorine substituents, or substituted, forexample by one, two, three, four, five, six, seven, eight, nine, ten oreleven fluorine substituents, or by one, two, three, four, five or sixfluorine substituents, or by one, two, three or four fluorinesubstituents, or by one or two fluorine substituents. The fluorinesubstituents can be located in any positions of the cycloalkyl group andcan also be located in an alkyl substituent on the cycloalkyl group.Examples of fluoro-substituted cycloalkyl groups are1-fluorocyclopropyl, 2,2-difluorocyclopropyl, 3,3-difluorocyclobutyl,1-fluorocyclohexyl, 4,4-difluorocyclohexyl and3,3,4,4,5,5-hexafluorocyclohexyl. Cycloalkyl groups can also besubstituted simultaneously by fluorine and alkyl. Halogen is fluorine,chlorine, bromine or iodine. In one embodiment of the invention, halogenin any occurrence in the compounds of the formula I, independently ofall other occurrences, is fluorine, chlorine or bromine, in anotherembodiment fluorine or chlorine, in another embodiment fluorine.

An oxo substituent, i.e. an oxygen atom which is bonded via a doublebond, when bonded to a carbon atom, replaces two hydrogen atoms on thecarbon atom of the parent system to which it is bonded. Thus, if a CH₂group is substituted by oxo, it becomes a carbonyl group (C(O), C═O). Anoxo substituent cannot be present on a carbon atom in an aromatic ring.

The present invention comprises all stereoisomeric forms of thecompounds of the formula I, for example all enantiomers anddiastereomers including cis/trans isomers. The invention likewisecomprises mixtures of two or more stereoisomeric forms, for examplemixtures of enantiomers and/or diastereomers including cis/transisomers, in all ratios. Asymmetric centers contained in the compounds ofthe formula I, for example in unsubstituted or substituted alkyl groups,can all independently of each other have the S configuration or the Rconfiguration. The invention relates to enantiomers, both thelevorotatory and the dextrorotatory antipode, in enantiomerically pureform and essentially enantiomerically pure form, for example with amolar ratio of the two enantiomers of 99:1 or greater, and in the formof racemates and in the form of mixtures of the two enantiomers in allratios. The invention likewise relates to diastereomers in the form ofpure and essentially pure diastereomers and in the form of mixtures oftwo or more diastereomers in all ratios. The invention also comprisesall cis/trans isomers of the compounds of the formula I in pure form andessentially pure form, for example with a molar ratio of the cis/transisomers of 99:1 or greater, and in the form of mixtures of the cisisomer and the trans isomer in all ratios. Cis/trans isomerism can occurin substituted rings. The preparation of individual stereoisomers, ifdesired, can be carried out by resolution of a mixture according tocustomary methods, for example, by chromatography or crystallization, orby use of stereochemically uniform starting compounds in the synthesisor by stereoselective reactions. Optionally, before a separation ofstereoisomers a derivatization can be carried out. The separation of amixture of stereoisomers can be carried out at the stage of the compoundof the formula I or at the stage of an intermediate in the course of thesynthesis. The invention also comprises all tautomeric forms of thecompounds of the formula I.

Physiologically acceptable salts, including pharmaceutically utilizablesalts, of the compounds of the formula I generally comprise a nontoxicsalt component. They can contain inorganic or organic salt components.Such salts can be formed, for example, from compounds of the formula Iwhich contain an acidic group, for example a carboxylic acid group(hydroxycarbonyl group, HO—C(O)—), and nontoxic inorganic or organicbases. Suitable bases are, for example, alkali metal compounds oralkaline earth metal compounds, such as sodium hydroxide, potassiumhydroxide, sodium carbonate or sodium hydrogencarbonate, or ammonia,organic amino compounds and quaternary ammonium hydroxides. Reactions ofcompounds of the formula I with bases for the preparation of the saltsare in general carried out according to customary procedures in asolvent or diluent. Examples of salts of acidic groups thus are sodium,potassium, magnesium or calcium salts or ammonium salts which can alsocarry one or more organic groups on the nitrogen atom. Compounds of theformula I which contain a basic, i.e. protonatable, group, for examplean amino group or a basic heterocycle, can be present in the form oftheir acid addition salts with physiologically acceptable acids, forexample as salt with hydrogen chloride, hydrogen bromide, phosphoricacid, sulfuric acid, acetic acid, benzoic acid, methanesulfonic acid,p-toluenesulfonic acid, which in general can be prepared from thecompounds of the formula I by reaction with an acid in a solvent ordiluent according to customary procedures. If the compounds of theformula I simultaneously contain an acidic and a basic group in themolecule, the invention also includes internal salts (betaines,zwitterions) in addition to the salt forms mentioned. The presentinvention also comprises all salts of the compounds of the formula Iwhich, because of low physiological tolerability, are not directlysuitable for use as a pharmaceutical, but are suitable as intermediatesfor chemical reactions or for the preparation of physiologicallyacceptable salts, for example by means of anion exchange or cationexchange. The present invention also comprises all solvates of thecompounds of the formula I and their salts, including physiologicallyacceptable solvates, such as hydrates, i.e. adducts with water, andadducts with alcohols like (C₁-C₄)-alkanols, as well as activemetabolites of compounds of the formula I and prodrugs of the compoundsof the formula I, i.e. compounds which in vitro may not necessarilyexhibit pharmacological activity but which in vivo are converted intopharmacologically active compounds of the formula I, for examplecompounds which are converted by metabolic hydrolysis into a compound ofthe formula I, such as compounds in which a carboxylic acid group ispresent in esterified form or in the form of an amide.

A subject of the invention are all compounds of the formula I whereinany one or more structural elements such as groups, substituents andnumbers are defined as in any of the specified embodiments ordefinitions of the elements or have one or more of the specific meaningswhich are mentioned herein as examples of elements, wherein allcombinations of one or more specified embodiments and/or definitionsand/or specific meanings of the elements are a subject of the presentinvention. Also with respect to all such compounds of the formula I, alltheir stereoisomeric forms and mixtures of stereoisomeric forms in anyratios, and their physiologically acceptable salts, and thephysiologically acceptable solvates of any of them, are a subject of thepresent invention.

A subject of the invention also is a compound of the formula I which ischosen from any of the specific compounds of the formula I which aredisclosed herein, or is any one of the specific compounds of the formulaI which are disclosed herein, irrespective thereof whether they aredisclosed as a free compound and/or as a specific salt, or aphysiologically acceptable salt thereof, or a physiologically acceptablesolvate of any of them, wherein the compound of the formula I is asubject of the invention in any of its stereoisomeric forms or a mixtureof stereoisomeric forms in any ratio.

Another subject of the present invention are the novel startingcompounds and intermediates occurring in the synthesis of the compoundsof the formula I, in any of their stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, and their salts, and solvates of anyof them, and their use as synthetic intermediates or starting compounds.All general explanations, specifications of embodiments and definitionsof numbers and groups given above with respect to the compounds of theformula I apply correspondingly to the said intermediates and startingcompounds. A subject of the invention are in particular the novelspecific starting compounds and intermediates described herein.Independently thereof whether they are described as a free compoundand/or as a specific salt, they are a subject of the invention both inthe form of the free compounds and in the form of their salts, and if aspecific salt is described, additionally in the form of this specificsalt.

The compounds of the formula I inhibit the protease cathepsin A as canbe demonstrated in the pharmacological test described below and in othertests which are known to a person skilled in the art. The compounds ofthe formula I and their physiologically acceptable salts and solvatestherefore are valuable pharmaceutical active compounds. The compounds ofthe formula I and their physiologically acceptable salts and solvatescan be used for the treatment of cardiovascular diseases such as heartfailure including systolic heart failure, diastolic heart failure,diabetic heart failure and heart failure with preserved ejectionfraction, cardiomyopathy, myocardial infarction, left ventriculardysfunction including left ventricular dysfunction after myocardialinfarction, cardiac hypertrophy, myocardial remodeling includingmyocardial remodeling after infarction or after cardiac surgery,valvular heart diseases, vascular hypertrophy, vascular remodelingincluding vascular stiffness, hypertension including pulmonaryhypertension, portal hypertension and systolic hypertension,atherosclerosis, peripheral arterial occlusive disease (PAOD),restenosis, thrombosis and vascular permeability disorders, ischemiaand/or reperfusion damage including ischemia and/or reperfusion damageof the heart and ischemia and/or reperfusion damage of the retina,inflammation and inflammatory diseases such as rheumatoid arthritis andosteoarthritis, renal diseases such as renal papillary necrosis andrenal failure including renal failure after ischemia/reperfusion,pulmonary diseases such as cystic fibrosis, chronic bronchitis, chronicobstructive pulmonary disease (COPD), asthma, acute respiratory dystresssyndrome (ARDS), respiratory tract infections and lung carcinoma,immunological diseases, diabetic complications including diabeticnephropathy and diabetic cardiomyopathy, fibrotic diseases such aspulmonary fibrosis including idiopathic lung fibrosis, cardiac fibrosis,vascular fibrosis, perivascular fibrosis, renal fibrosis including renaltubulointerstitial fibrosis, fibrosing skin conditions including keloidformation, collagenosis and scleroderma, and liver fibrosis, liverdiseases such as liver cirrhosis, pain such as neuropathic pain,diabetic pain and inflammatory pain, macular degeneration,neurodegenerative diseases or psychiatric disorders, or forcardioprotection including cardioprotection after myocardial infarctionand after cardiac surgery, or for renoprotection, for example. Thecompounds of the formula I and their physiologically acceptable saltsand solvates can be used as a diuretic (stand-alone treatment or incombination with established diuretics). The compounds of the formula Iand their physiologically acceptable salts and solvates can also be usedfor treatment and/or prevention of atrial fibrillation. The treatment ofdiseases is to be understood as meaning both the therapy of existingpathological changes or malfunctions of the organism or of existingsymptoms with the aim of relief, alleviation or cure, and theprophylaxis or prevention of pathological changes or malfunctions of theorganism or of symptoms in humans or animals which are susceptiblethereto and are in need of such a prophylaxis or prevention, with theaim of a prevention or suppression of their occurrence or of anattenuation in the case of their occurrence. For example, in patientswho on account of their disease history are susceptible to myocardialinfarction, by means of the prophylactic or preventive medicinaltreatment the occurrence or re-occurrence of a myocardial infarction canbe prevented or its extent and sequelae decreased, or in patients whoare susceptible to attacks of asthma, by means of the prophylactic orpreventive medicinal treatment such attacks can be prevented or theirseverity decreased. The treatment of diseases can occur both in acutecases and in chronic cases. The efficacy of the compounds of the formulaI can be demonstrated in the pharmacological test described below and inother tests which are known to a person skilled in the art.

The compounds of the formula I and their physiologically acceptablesalts and solvates can therefore be used in animals, in particular inmammals and specifically in humans, as a pharmaceutical or medicament ontheir own, in mixtures with one another or in the form of pharmaceuticalcompositions. A subject of the present invention also are the compoundsof the formula I and their physiologically acceptable salts and solvatesfor use as a pharmaceutical, as well as pharmaceutical compositions andmedicaments which comprise an efficacious dose of at least one compoundof the formula I and/or a physiologically acceptable salt thereof and/orsolvate thereof as an active ingredient and a pharmaceuticallyacceptable carrier, i.e. one or more pharmaceutically innocuous, ornonhazardous, vehicles and/or excipients, and optionally one or moreother pharmaceutical active compounds. A subject of the presentinvention furthermore are the compounds of the formula I and theirphysiologically acceptable salts and solvates for use in the treatmentof the diseases mentioned above or below, including the treatment of anyone of the mentioned diseases, for example the treatment of heartfailure, myocardial infarction, cardiac hypertrophy, diabeticnephropathy, diabetic cardiomyopathy, cardiac fibrosis, or ischemiaand/or reperfusion damage, or for cardioprotection, the use of thecompounds of the formula I and their physiologically acceptable saltsand solvates for the manufacture of a medicament for the treatment ofthe diseases mentioned above or below, including the treatment of anyone of the mentioned diseases, for example the treatment of heartfailure, myocardial infarction, cardiac hypertrophy, diabeticnephropathy, diabetic cardiomyopathy, cardiac fibrosis, or ischemiaand/or reperfusion damage, or for cardioprotection, wherein thetreatment of diseases comprises their therapy and prophylaxis asmentioned above, as well as their use for the manufacture of amedicament for the inhibition of cathepsin A. A subject of the inventionalso are methods for the treatment of the diseases mentioned above orbelow, including the treatment of any one of the mentioned diseases, forexample the treatment of heart failure, myocardial infarction, cardiachypertrophy, diabetic nephropathy, diabetic cardiomyopathy, cardiacfibrosis, or ischemia and/or reperfusion damage, or forcardioprotection, which comprise administering an efficacious amount ofat least one compound of the formula I and/or a physiologicallyacceptable salt thereof and/or solvate thereof to a human or an animalwhich is in need thereof. The compounds of the formula I andpharmaceutical compositions and medicaments comprising them can beadministered enterally, for example by oral, sublingual or rectaladministration, parenterally, for example by intravenous, intramuscular,subcutaneous or intraperitoneal injection or infusion, or by anothertype of administration such as topical, percutaneous, transdermal,intra-articular or intraocular administration.

The compounds of the formula I and their physiologically acceptablesalts and solvates can also be used in combination with otherpharmaceutical active compounds, wherein in such a combination use thecompounds of the formula I and/or their physiologically acceptable saltsand/or solvates and one or more other pharmaceutical active compoundscan be present in one and the same pharmaceutical composition or in twoor more pharmaceutical compositions for separate, simultaneous orsequential administration. Examples of such other pharmaceutical activecompounds are diuretics, aquaretics, angiotensin converting enzyme (ACE)inhibitors, angiotensin receptor blockers, renin inhibitors, betablockers, digoxin, aldosterone antagonists, NO donors, nitrates,hydralazines, ionotropes, vasopressin receptor antagonists, solubleguanylate cyclase activators, statins, peroxisome proliferator-activatedreceptor-alpha (PPAR-α) activators, peroxisome proliferator-activatedreceptor-gamma (PPAR-γ) activators, rosiglitazone, pioglitazone,metformin, sulfonylureas, glucagon-like peptide 1 (GLP-1) agonists,dipeptidyl peptidase IV (DPPIV) inhibitors, insulins, anti-arrhythmics,endothelin receptor antagonists, calcium antagonists, phosphodiesteraseinhibitors, phosphodiesterase type 5 (PDE5) inhibitors, factor II/factorIIa inhibitors, factor IX/factor IXa inhibitors, factor X/factor Xainhibitors, factor XIII/factor XIIIa inhibitors, heparins, glycoproteinIIb/IIIa antagonists, P2Y12 receptor antagonists, clopidogrel,coumarins, cyclooxygenase inhibitors, acetylsalicylic acid, RAF kinaseinhibitors and p38 mitogen-activated protein kinase inhibitors. Asubject of the present invention also is the said combination use of anyone or more of the compounds of the formula I disclosed herein and theirphysiologically acceptable salts and solvates, with any one or more, forexample one or two, of the mentioned other pharmaceutical activecompounds.

The pharmaceutical compositions and medicaments according to theinvention normally contain from about 0.5 to about 90 percent by weightof compounds of the formula I and/or physiologically acceptable saltsand/or solvates thereof, and an amount of active ingredient of theformula I and/or its physiologically acceptable salt and/or solvatewhich in general is from about 0.2 mg to about 1.5 g, particularly fromabout 0.2 mg to about 1 g, more particularly from about 0.5 mg to about0.5 g, for example from about 1 mg to about 0.3 g, per unit dose.Depending on the kind of the pharmaceutical composition and otherparticulars of the specific case, the amount may deviate from theindicated ones. The production of the pharmaceutical compositions andmedicaments can be carried out in a manner known per se. For this, thecompounds of the formula I and/or their physiologically acceptable saltsand/or solvates are mixed together with one or more solid or liquidvehicles and/or excipients, if desired also in combination with one ormore other pharmaceutical active compounds such as those mentionedabove, and brought into a suitable form for dosage and administration,which can then be used in human medicine or veterinary medicine.

As vehicles, which may also be looked upon as diluents or bulkingagents, and excipients suitable organic and inorganic substances can beused which do not react in an undesired manner with the compounds of theformula I. As examples of types of excipients, or additives, which canbe contained in the pharmaceutical compositions and medicaments,lubricants, preservatives, thickeners, stabilizers, disintegrants,wetting agents, agents for achieving a depot effect, emulsifiers, salts,for example for influencing the osmotic pressure, buffer substances,colorants, flavorings and aromatic substances may be mentioned. Examplesof vehicles and excipients are water, vegetable oils, waxes, alcoholssuch as ethanol, isopropanol, 1,2-propanediol, benzyl alcohols,glycerol, polyols, polyethylene glycols or polypropylene glycols,glycerol triacetate, polyvinylpyrrolidone, gelatin, cellulose,carbohydrates such as lactose or starch like corn starch, sodiumchloride, stearic acid and its salts such as magnesium stearate, talc,lanolin, petroleum jelly, or mixtures thereof, for example saline ormixtures of water with one or more organic solvents such as mixtures ofwater with alcohols. For oral and rectal use, pharmaceutical forms suchas, for example, tablets, film-coated tablets, sugar-coated tablets,granules, hard and soft gelatin capsules, suppositories, solutions,including oily, alcoholic or aqueous solutions, syrups, juices or drops,furthermore suspensions or emulsions, can be used. For parenteral use,for example by injection or infusion, pharmaceutical forms such assolutions, for example aqueous solutions, can be used. For topical use,pharmaceutical forms such as ointments, creams, pastes, lotions, gels,sprays, foams, aerosols, solutions or powders can be used. Furthersuitable pharmaceutical forms are, for example, implants and patches andforms adapted to inhalation. The compounds of the formula I and theirphysiologically acceptable salts can also be lyophilized and theobtained lyophilizates used, for example, for the production ofinjectable compositions. In particular for topical application, alsoliposomal compositions are suitable. The pharmaceutical compositions andmedicaments can also contain one or more other active ingredientsand/or, for example, one or more vitamins.

As usual, the dosage of the compounds of the formula I depends on thecircumstances of the specific case and is adjusted by the physicianaccording to the customary rules and procedures. It depends, forexample, on the compound of the formula I administered and its potencyand duration of action, on the nature and severity of the individualsyndrome, on the sex, age, weight and the individual responsiveness ofthe human or animal to be treated, on whether the treatment is acute orchronic or prophylactic, or on whether further pharmaceutical activecompounds are administered in addition to a compound of the formula I.Normally, in the case of administration to an adult weighing about 75kg, a dose from about 0.1 mg to about 100 mg per kg per day, inparticular from about 1 mg to about 20 mg per kg per day, for examplefrom about 1 mg to about 10 mg per kg per day (in each case in mg per kgof body weight), is administered. The daily dose can be administered inthe form of a single dose or divided into a number of individual doses,for example two, three or four individual doses. The administration canalso be carried out continuously, for example by continuous injection orinfusion.

Depending on the individual behavior in a specific case, it may benecessary to deviate upward or downward from the indicated dosages.

Besides as a pharmaceutical active compound in human medicine andveterinary medicine, the compounds of the formula I can also be employedas an aid in biochemical investigations or as a scientific tool or fordiagnostic purposes, for example in in-vitro diagnoses of biologicalsamples, if an inhibition of cathepsin A is intended. The compounds ofthe formula I and their salts can also be used as intermediates, forexample for the preparation of further pharmaceutical active substances.

The following examples illustrate the invention.

Abbreviations

ACN acetonitrile

DCM dichloromethane

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

EA ethyl acetate

EDIA N-ethyl-diisopropylamine

FA formic acid

MOH methanol

NEM N-ethyl-morpholine

TFA trifluoroacetic acid

THF tetrahydrofuran

TOTUO—(cyano(ethoxycarbonyl)methyleneamino)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate

When example compounds containing a basic group were purified bypreparative high pressure liquid chromatography (HPLC) on reversed phase(RP) column material and, as customary, the eluent was a gradientmixture of water and acetonitrile containing trifluoroacetic acid, theywere in part obtained in the form of their acid addition salts withtrifluoroacetic acid, depending on the details of the work-up such asevaporation or lyophilization conditions. In the names of the examplecompounds and the structural formulae such contained trifluoroaceticacid is not specified. Likewise are other acid components of examplecompounds obtained in the form of an acid addition salt in general notspecified in the name and the formula.

The prepared compounds were in general characterized by spectroscopicdata and chromatographic data, in particular mass spectra (MS) and HPLCretention times (Rt; in min) which were obtained by combined analyticalHPLC/MS characterization (LC/MS), and/or nuclear magnetic resonance(NMR) spectra. Unless specified otherwise, ¹H-NMR spectra were recordedat 500 MHz in D₆-DMSO as solvent at 298 K. In the NMR characterization,the chemical shift δ (in ppm), the number of hydrogen atoms (H), and themultiplicity (s: singlet, d: doublet, dd: doublet of doublets, t:triplet, q: quartet, m: multiplet) of the peaks as determined from thegraphically depicted spectra are given. In the MS characterization, ingeneral the mass number (m/z) of the peak of the molecular ion [M], forexample [M⁺], or of a related ion such as the ion [M+1], for example[(M+1)⁺], i.e. the protonated molecular ion [(M+H)⁺], or the ion [M−1],for example [(M−1)⁻], i.e. the deprotonated molecular ion [(M−H)⁻],which was formed depending on the ionization method used, is given.Generally, the ionization method was electrospray ionization (ES). Theparticulars of the LC/MS methods used are as follows.

Method LC1

Column: Waters UPLC BEH C18, 50×2.1 mm, 1.7 μm; flow: 0.9 ml/min; 55°C.; eluent A: water+0.05% FA; eluent B: ACN+0.035% FA; gradient: from98% A+2% B to 5% A+95% B within 2.0 min, then 5% A+95% B for 0.6 min,then to 95% A+5% B within 0.1 min, then 95% A+5% B for 0.3 min; MSionization method: ES⁺

Method LC2

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.7 ml/min; 40° C.;eluent A: water+0.05% TFA; eluent B: ACN+0.05% TFA; gradient: 95% A+5% Bfor 0.2 min, then to 5% A+95% B within 2.2 min, then 5% A+95% B for 0.8min, then to 95% A+5% B within 0.1 min, then 95% A+5% B for 0.7 min; MSionization method: ES⁺

Method LC3

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.7 ml/min; 40° C.;eluent A: water+0.1% TFA; eluent B: ACN+0.1% TFA; gradient: 97% A+3% Bfor 0.2 min, then to 40% A+60% B within 3.5 min, then to 2% A+98% Bwithin 0.5 min, then 2% A+98% B for 0.5 min, then to 97% A+3% B within0.2 min, then 97% A+3% B for 0.3 min; MS ionization method: ES⁺

EXPERIMENTAL

In general the compounds of formula I are synthesized according to oneof the general schemes below:

0.3 mmol boronic acid is placed in a reaction tube, 0.2 mmol of theintermediate A dissolved in 2 ml of DMF and 0.8 mmol Cs2CO3 dissolved in1 ml water is added and the reaction tube purged with Ar. After theaddition of 0.02 mmol mmol Pd[PPh3]Cl2 is reaction mixture is heatedovernight at 95° C.

The reaction mixture is adjusted to pH=5 with 2N HCl, 15 ml EtOAc and 5ml 5% NaCl solution are added, the organic phase is separated and driedover Na2SO4. The solvent is removed in vacuo and the crude productsubjected to HPLC chromatography. Yields are in the range from 10 to95%.

0.3 mmol boronic acid is placed in a reaction tube, 0.2 mmol of theintermediate D dissolved in 2 ml of DMF and 0.8 mmol Cs2CO3 dissolved in1 ml water is added and the reaction tube purged with Ar. After theaddition of 0.02 mmol mmol Pd[PPh3]Cl2 is reaction mixture is heatedovernight at 95° C.

The reaction mixture is adjusted to pH=5 with 2N HCl, 15 ml EtOAc and 5ml 5% NaCl solution are added, the organic phase is separated and driedover Na2SO4. The solvent is removed in vacuo, the crude product isdissolved in 2 ml EtOH and 0.5 ml 1N NaOH is added. After stirringovernight at RT the solvent is removed and the isolated material issubjected to HPLC chromatography. Yields are in the range from 10 to95%.

The Suzuki reactions described above can be carried out by allprocedures well known to a person skilled in the art and described forexample in M. Mora et. al. Current Organic Chemistry 2012, 1128-1150

Solvents other than DMF like isopropanol, toluene, dioxane, THF,acetonitrile, water or any combinations of them might be used, thereaction is also possible by using ionic liquids. Any combination of apalladium salt and ligand or any preformed palladium catalyst system canbe applied for these reactions. Polymer-bound Pd-catalysts orpolymer-bound ligands may also be used. As base one might use Na₂CO₃,K₂CO₃, AgCO₃ or CsF instead of Cs₂CO₃. The reaction temperatures are inthe range from 40° C. to 150° C. and may be reached by thermal heatingor by using a microwave reactor for a period from 5 minutes to 48 hours.

In scheme B one can isolate the product of the Suzuki coupling from thefirst step prior to the formation of the final product by esterhydrolysis or one can run both reactions in a one pot procedure withoutisolating the ester material. Instead of the ethyl ester in scheme B anyother ester known to people skilled in the art may be used. Althoughinstead of the triflate in scheme B one might use any other suitableleaving groups for Suzuki reactions.

Intermediates A are synthesized according to the general scheme C byaddition of a metallated five-membered heterocycle F to an aromatic acidderivative E: E can be an aromatic acid ester, an aromatic acid chlorideor a Weinreb amide of an aromatic carboxylic acid E. The resultingketone G is subjected to a Wittig reaction and the Wittig condensationproduct H is reduced by applying Zn/HOAc and the ester residue isconverted into the free acid A.

In the metallation step instead of n-BuLi tert-BuLi or MeLi a Grignardreagent like MeMgBr, iso-propyl-MgBr or iso-propyl-MgCl*LiCl may beused. To facilitate the addition to the intermediate E atransmetallation to another metal ion like copper or zinc might benecessary.

For the Wittig reaction one might use other strong bases instead of NaHlike NaOtBu or KOtBu or phosphazene bases. And the reduction might becarried out using Zn in aq. HCl using a concentration of aq. HCl rangingfrom 0.01M to 12M or in diluted H2SO4.

Intermediates E might be commercially available or might be prepared inone step from the commercially available carboxylic acids

Under certain circumstances the group Y might represent a hydrogen atomforming the aromatic aldehyde intermediate E-H. After the addition ofthe metallated heterocycle F the corresponding alcohol I can be oxidizedto the desired intermediate G by using MnO2 or other oxidants likeKMnO4, CrO3, and H2O2.

In an alternative approach to the synthesis described in scheme C, theresidue Hal in building block E might be replaced by a benzyloxy-residueleading to building block M. When the reduction of the CC-double bond ofthe Wittig condensation product O is carried out with Pd/C and H2 thebenzyl residue is removed at the same time. Conversion of the newlyformed aromatic hydroxy group into the triflate furnishes intermediateP, a suitable starting material for palladium catalyzed cross-couplings.The starting materials M can be obtained from aromatic carboxylic acidesters having a free hydroxy substituent like J. The hydroxy substituentis alkylated with benzylbromide, benzyl chloride or benzyl iodide or anyother benzyl derivative capable of undergoing a nucleophilicsubstitution reaction with an aromatic hydroxy group. Depending on thereactivity of the intermediate L towards the metallation reaction, Lmight be converted into the corresponding derivatives M by standardprocedures well known to a person skilled in the art.

Synthesis of Intermediate P13-(5-methylthiazol-2-yl)-3-(6-(trifluoromethyl-sulfonyloxy)pyridin-2-yl)propanoate

Step 1: Synthesis of methyl 6-hydroxypicolinate

To a solution of 6-hydroxypicolinic acid (13.0 g, 93.5 mmol) in methanol(150 mL) at room temperature was added HCl in dioxane (4N, 10 mL). Theresulting mixture was stirred at room temperature for 48 hours. Thereaction mixture was concentrated to give methyl 6-hydroxypicolinate (13g, 90%) as a white solid.

Synthesis of methyl 6-(benzyloxy)picolinate

A mixture of methyl 6-hydroxypicolinate (3.06 g, 20.0 mmol),(bromomethyl)benzene (6.84 g, 40.0 mmol), and silver carbonate (11 g, 40mmol) in toluene (150 mL) was stirred at 80° C. overnight. After coolingand filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography elutingwith petroleum ether/ethyl acetate (20:1) to give methyl6-(benzyloxy)picolinate (2.6 g, 53%) as a white solid.

Synthesis of (6-(benzyloxy)pyridin-2-yl)(5-methylthiazol-2-yl)methanone

To a solution of n-BuLi (2.5 M in hexane, 16 mL, 40 mmol) in dry THF(120 mL) at −78° C. was added 5-methylthiazole (4.17 g, 40 mmol) dropwise over 20 minutes under nitrogen atmosphere. The mixture was stirredat −78° C. for 2 hrs and a solution of methyl 6-(benzyloxy)picolinate(4.7 g, 20 mmol) in THF (30 mL) was added drop wise over 20 minutes.After being stirred at −78° C. for 1 hr, the mixture was acidified withHCl (1N) to pH around 6 and extracted with ethyl acetate. The organiclayer was concentrated and then diluted with MTBE. The white precipitatewas collected by filtration to give A030-4. The remaining filtrate wasconcentrated. The residue was purified by silica gel chromatographyeluting with petroleum ether/ethyl acetate (10/1) to afford A030-4.Total 6.2 g of(6-(benzyloxy)pyridin-2-yl)(5-methylthiazol-2-yl)methanone (85% yield)was obtained as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J=7.2 Hz, 1H), 7.89 (s, 1H), 7.82 (t,J=8.0 Hz, 1H), 7.51-7.36 (m, 5H), 7.01 (d, J=8.0 Hz, 1H), 5.56 (s, 2H),2.60 (s, 3H).

Synthesis of (Z)-ethyl3-(6-(benzyloxy)pyridin-2-yl)-3-(5-methylthiazol-2-yl)acrylate

To a suspension of NaH (60%, 1.3 g, 33 mmol) in dry THF (200 mL) at −78°C. was added ethyl 2-(diethoxyphosphoryl)acetate (7.5 g, 33 mmol). Afterbeing stirred at −78° C. for 1 hour, a solution of(6-(benzyloxy)pyridin-2-yl)(5-methylthiazol-2-yl)methanone (3.47 g, 11.2mmol) in THF (30 mL) was added drop wise over 30 minutes. After beingstirred at −20 to −30° C. for 2 hours, the mixture was acidified withHCl (0.5 N) and then extracted with ethyl acetate. The organic layer wasdried and concentrated. The residue was washed with MTBE and petroleumether to afford(6-(benzyloxy)pyridin-2-yl)(5-methylthiazol-2-yl)methanone (6.2 g, 85%yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.58-7.25 (m, 8H), 6.80 (d, J=8.4 Hz, 1H),6.75 (d, J=7.2 Hz, 1H), 5.44 (s, 2H), 4.15 (q, J=3.2 Hz, 2H), 2.54 (s,3H), 1.21 (t, J=3.2 Hz, 3H).

Synthesis of ethyl3-(6-hydroxypyridin-2-yl)-3-(5-methylthiazol-2-yl)propanoate

A mixture of (6-(benzyloxy)pyridin-2-yl)(5-methylthiazol-2-yl)methanone(8.0 g, 21 mmol), acetic acid (1.5 mL), H₂O (3 mL), and Pd/C (10%, 4 g)in ethanol (90 mL) and THF (60 mL) was stirred under H₂ atmosphere atroom temperature overnight. After filtration through a pad of Celite andevaporation of the solvent, the residue was washed with MTBE andpetroleum ether to afford A030-7 (3 g) as a white solid. The filtration(mixture of A030-6 and A030-7) was mixed with TFA (20 mL) and theresulting mixture was refluxed for 2 h. After cooling down, the mixturewas treated with water and extracted with ethyl acetate. The organiclayer was dried and concentrated. The residue was washed with MTBE andpetroleum ether to afford ethyl3-(6-hydroxypyridin-2-yl)-3-(5-methylthiazol-2-yl)propanoate (1.4 g,total 71%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.40 (s, 1H), 7.34-7.30 (m, 1H), 6.46 (dd,J=9.2, 1.2 Hz, 1H), 6.14 (d, J=6.0 Hz, 1H), 4.63 (t, J=7.2 Hz, 1H),4.13-4.07 (m, 2H), 3.25-3.19 (m, 1H), 3.05-2.97 (m, 1H), 2.43 (s, 3H),1.19 (t, J=3.2 Hz, 3H).

Synthesis of ethyl3-(5-methylthiazol-2-yl)-3-(6-(trifluoromethylsulfonyloxy)pyridin-2-yl)propanoate

To a solution of ethyl3-(6-hydroxypyridin-2-yl)-3-(5-methylthiazol-2-yl)propanoate (3.45 g,11.8 mmol) in DCM (200 mL) at −78° C. was added trifluoromethanesulfonicanhydride (5.00 g, 17.7 mmol) and DIPEA (5.00 mL, 23.6 mmol) drop wiseover 30 minutes. The resulting mixture was stirred at −78° C. for 30minutes and warmed to room temperature overnight. The mixture was cooledto 0° C. and treated with water (100 mL). The organic layer was driedover Na₂SO₄ and concentrated. The oily residue was treated with etherand the solid was filtered off. The filtrate was concentrated to affordethyl3-(5-methylthiazol-2-yl)-3-(6-(trifluoromethylsulfonyloxy)pyridin-2-yl)propanoate(4.6 g, 93%) as brown oil.

¹H NMR (400 MHz, CDCl₃) δ 7.83 (t, J=7.6 Hz, 1H), 7.42 (d, J=7.6 Hz,1H), 7.33 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 5.02-4.99 (m, 1H), 4.08 (q,J=3.2 Hz, 2H), 3.41-3.35 (m, 1H), 3.22-3.16 (m, 1H), 2.41 (s, 3H), 1.18(t, J=3.2 Hz, 3H).

Synthesis of Intermediate P2 Ethyl3-(5-methylthiazol-2-yl)-3-(5-(trifluoromethylsulfonyloxy)pyridin-3-yl)-propanoate

Synthesis of methyl 5-hydroxynicotinate

To a stirred solution of 5-hydroxynicotinic acid (10 g, 71.9 mmol) inMeOH (100 mL) was added sulfurous dichloride (1 mL) drop wise over 5min. The resulting mixture was stirred at room temperature overnight.The resulted solution was added 100 mL of NaHCO₃. The precipitate wasfiltrated and washed with MeOH for several cycles to give 8.5 g ofA031-2 (75% yields), which was used for the nest step without furtherpurification.

Synthesis of methyl 5-(benzyloxy)nicotinate

To a stirred solution of methyl 5-hydroxynicotinate (8.5 g, 55.6 mmol)and K₂CO₃ (11.5 g, 83.3 mmol) in DMF (20 mL) at 0° C. was added(bromomethyl)benzene (8 mL, 66.7 mmol) drop wise over 5 min. Theresulting mixture was stirred at room temperature for 2 hours. Themixture was quenched with water (100 mL) and extracted with EA (100mL×3). The combined organic layers were washed with brine (100 mL),dried over Na₂SO₄. After filtration and evaporation of the solvent, theresidue was purified by silica gel column chromatography eluting withpetroleum ether/ethyl acetate (4:1) to give methyl5-(benzyloxy)nicotinate (4 g, 30.7%) as a yellow oil.

Synthesis of (5-(benzyloxy)pyridin-3-yl)(5-methylthiazol-2-yl)methanone

To a stirring mixture of 5-methylthiazole (3.3 g, 33 mmol) in dry THF(20 mL) was added n-BuLi (33 mmol 13.2 mL solution in hexanes,) dropwise over 10 minutes at −78° C. under nitrogen atmosphere. The mixturewas stirred between −78° C. and −60° C. for 1.5 h and then cooled to−78° C. A solution of methyl 5-(benzyloxy)nicotinate (4.0 g, 16.5 mmol)in THF (10 mL) was added drop wise over 10 minutes. The resultingmixture was stirred at −78° C. for 30 minutes and warmed to roomtemperature with stirring overnight. The mixture was cooled to 0° C. andtreated with water (50 mL). The resulting mixture was adjusted to pHaround 6 with HCl (1N) and extracted with EA (100 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography eluting with petroleum ether/EtOAc (3:1) to afford(5-(benzyloxy)-2-methoxyphenyl)(thiazol-2-yl)methanone (3.2 g, 42%) as ayellow gel.

Synthesis of (Z)-ethyl3-(5-(benzyloxy)pyridin-3-yl)-3-(5-methylthiazol-2-yl)acrylate

To a suspension of NaH (60%, 1.2 g, 30.9 mmol) in dry THF (20 mL) wasadded ethyl 2-(diethoxyphosphoryl)acetate (6.9 g, 30.9 mmol) at −78° C.After being stirred at −78° C. for 1 hour, a solution of(5-(benzyloxy)pyridin-3-yl)(5-methylthiazol-2-yl)methanone (3.2 g, 10.3mmol) in THF (5 mL) was added drop wise over 30 min. The mixture wasstirred at −78° C. for 30 min and then warmed to room temperature withstirring overnight. The mixture was cooled to 0° C. and treated withwater (50 mL), pH value was adjusted to 6 with HCl (0.5 N) and extractedwith EA (50 mL×3). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with petroleum ether/EtOAc(3:1) to afford (Z)-ethyl3-(5-(benzyloxy)-2-methoxyphenyl)-3-(thiazol-2-yl)acrylate (3.1 g,80.0%) as yellow gel.

Synthesis of ethyl3-(5-hydroxypyridin-3-yl)-3-(5-methylthiazol-2-yl)propanoate

To a mixture of (Z)-ethyl3-(5-(benzyloxy)pyridin-3-yl)-3-(5-methylthiazol-2-yl)acrylate (3.1 g,8.2 mmol), HOAc (1.0 mL), and H₂O (2.0 mL) in EtOH (20 mL) and THF (10mL) was added Pd/C (10%, dry, 820 mg) under H2 atmosphere. The mixturewas stirred at room temperature under H₂ atmosphere for 48 hrs. Afterfiltration through a pad of Celite and evaporation of the solvent, theresidue was purified by silica gel chromatography eluting with petroleumether/EtOAc (3:1) to afford3-(5-hydroxypyridin-3-yl)-3-(5-methylthiazol-2-yl)propanoate (2.2 g,92%) as a yellow-green gel.

Synthesis of ethyl3-(5-methylthiazol-2-yl)-3-(5-(trifluoromethylsulfonyloxy)pyridin-3-yl)propanoate

To a stirred solution of ethyl3-(5-hydroxypyridin-3-yl)-3-(5-methylthiazol-2-yl)propanoate (2.2 g, 7.5mmol) and Et₃N (1.52 g, 15.1 mmol) in DCM (20 mL) at −78° C. was addedtrifluoromethanesulfonic anhydride (2.3 g, 15.1 mmol) drop wise over 5min. The resulting mixture was stirred at −78° C. for 30 minutes andwarmed to room temperature with stirring overnight. The mixture wascooled to 0° C., treated with water (50 mL) and extracted with DCM (50mL×3). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, and concentrated. The residue was purified by silica gelcolumn chromatography eluting with petroleum ether/ethyl acetate (4:1)to give ethyl3-(2-methoxy-5-(trifluoromethylsulfonyloxy)phenyl)-3-(thiazol-2-yl)propanoate(900 mg, 28.0%) as yellow oil.

¹H NMR (400 MHz, MeOD) δ 8.71 (d, J=1.2 Hz, 1H), 8.58 (d, J=2.4 Hz, 1H),7.96 (s, 1H), 7.43 (s, 1H), 5.02 (t, 1H), 4.10-4.05 (m, 2H), 3.43-3.37(m, 1H), 3.22-3.15 (m, 1H), 2.45 (s, 3H), 1.18-1.14 (m, 3H).

Synthesis of Intermediate P33-(2-Methoxy-5-trifluoromethanesulfonyloxy-phenyl)-3-(5-methyl-thiazol-2-yl)-propionicacid ethyl ester

Methyl 5-(benzyloxy)-2-hydroxybenzoate

To a refluxed suspension of K₂CO₃ (32.8 g, 238 mmol) in methanol (180mL) and CHCl₃ (350 mL) was then added a mixture of methyl2,5-dihydroxybenzoate (10.0 g, 59.5 mmol) and bromomethylbenzene (7.10mL, 59.5 mmol) in methanol/CHCl₃ (50 mL/25 mL) drop wise over 30minutes. The resulting mixture was stirred at reflux for another 4hours. After cooling down and filtration, the filter cake was washedwith CHCl₃ (20 mL). The combined filtrate was concentrated under reducedpressure. The residue was redissolved in CHCl₃ (200 mL), washed with HCl(1N) (100 mL×2). The organic was then washed with brine (100 mL), driedover Na₂SO₄, filtered, and concentrated. The residue was purified bysilica gel column chromatography eluting with petroleum ether/EtOAc(8:1) to give methyl 5-(benzyloxy)-2-hydroxybenzoate (10.6 g, 69.0%) asa white solid.

¹H NMR (500 MHz DMSO-d₆) δ 10.09 (s, 1H), 7.43 (d, J=7.2 Hz, 2H),7.40-7.36 (m, 2H), 7.34-7.32 (2H, m), 7.23 (dd, J=9.2, 3.2 Hz, 1H), 6.93(d, J=9.2 Hz, 1H), 5.06 (s, 2H), 3.88 (s, 3H). NOESY showed the desiredproduct as well.

Methyl 5-(benzyloxy)-2-methoxybenzoate

To a mixture of methyl 5-(benzyloxy)-2-hydroxybenzoate (10.6 g, 41.1mmol) and K₂CO₃ (11.3 g, 82.2 mmol) in DMF (100 mL) was addediodomethane (2.60 mL, 49.3 mmol) drop wise over 5 minutes. The resultingmixture was stirred at room temperature overnight. The reaction mixturewas poured into water (400 mL), filtered, and collected the solid. Thesolid was dissolved in EtOAc (300 mL), washed with water (50 mL) andbrine (100 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure to give methyl 5-(benzyloxy)-2-methoxybenzoate (10.4 g,98%) as a yellow solid.

(5-(benzyloxy)-2-methoxyphenyl)(5-methylthiazol-2-yl)methanone

To a stirring mixture of 5-methylthiazole (3.80 g, 38.2 mmol) in dry THF(200 mL) was added n-BuLi (2.5 M in hexane, 15.3 mL, 38.2 mmol) dropwise over 20 minutes at −78° C. under nitrogen atmosphere. The mixturewas stirred between −78° C. and −60° C. for 1.5 h and then cooled to−78° C. A solution of methyl 5-(benzyloxy)-2-methoxybenzoate (10.4 g,38.2 mmol) in THF (50 mL) was added drop wise over 30 minutes. Theresulting mixture was stirred at −78° C. for 30 minutes and warmed toroom temperature with stirring overnight. The mixture was cooled to 0°C. and treated with water (50 mL). The resulting mixture was adjusted topH around 6 with HCl (1N). The organic layer was dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography eluting with petroleumether/EtOAc (3:1) to afford(5-(benzyloxy)-2-methoxyphenyl)(5-methylthiazol-2-yl)methanone (2.5 g,19%) as a yellow gel. 3.0 g of starting material methyl5-(benzyloxy)-2-methoxybenzoate was recovered.

Synthesis of (Z)-ethyl3-(5-(benzyloxy)-2-methoxyphenyl)-3-(5-methylthiazol-2-yl)acrylate

To a suspension of NaH (60%, 884 mg, 22.1 mmol) in dry THF (120 mL) wasadded ethyl 2-(diethoxyphosphoryl)acetate (4.96 g, 22.1 mmol) at −78° C.After being stirred at −78° C. for 1 hour, a solution of(5-(benzyloxy)-2-methoxyphenyl)(5-methylthiazol-2-yl)methanone (2.50 g,7.37 mmol) in THF (30 mL) was added drop wise over 30 min. The mixturewas stirred at −78° C. for 30 min and then warmed to room temperaturewith stirring overnight. The mixture was cooled to 0° C. and treatedwith water (50 mL), pH value was adjusted to 6 with HCl (0.5 N). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with petroleum ether/EtOAc (3:1) to afford (Z)-ethyl3-(5-(benzyloxy)-2-methoxyphenyl)-3-(5-methylthiazol-2-yl)acrylate (1.75g, 58.0%) as yellow gel.

Synthesis of ethyl3-(5-hydroxy-2-methoxyphenyl)-3-(5-methylthiazol-2-yl)-propanoate

To a mixture of (Z)-ethyl3-(5-(benzyloxy)-2-methoxyphenyl)-3-(5-methylthiazol-2-yl)acrylate (4.0g, 9.8 mmol), HOAc (2.0 mL), and H₂O (5.0 mL) in EtOH (100 mL) and THF(60 mL) was added Pd/C (10%, dry, 5.0 g) under nitrogen atmosphere. Themixture was stirred at room temperature under H₂ atmosphere for 48 hrs.After filtration through a pad of Celite and evaporation of the solvent,the residue was purified by silica gel chromatography eluting withpetroleum ether/EtOAc (3:1) to afford ethyl3-(5-hydroxy-2-methoxyphenyl)-3-(5-methylthiazol-2-yl)propanoate (1.9 g,60%) as a yellow-green gel.

Ethyl-3-(2-methoxy-5-(trifluoromethylsulfonyloxy)phenyl)-3-(5-methylthiazol-2-yl)propanoate

To a stirred solution of ethyl3-(5-hydroxy-2-methoxyphenyl)-3-(5-methylthiazol-2-yl)propanoate (4.50g, 14.0 mmol) and DIPEA (4.8 mL, 28 mmol) in DCM (150 mL) at −78° C. wasadded trifluoromethanesulfonic anhydride (4.74 g, 16.8 mmol) drop wiseover 30 min. The resulting mixture was stirred at −78° C. for 30 minutesand warmed to room temperature with stirring overnight. The mixture wascooled to 0° C. and treated with water (50 mL). The organic layer waswashed with brine (50 mL), dried over Na₂SO₄, and concentrated. Theresidue was purified by silica gel column chromatography eluting withpetroleum ether/ethyl acetate (4:1) to give ethyl3-(2-methoxy-5-(trifluoromethylsulfonyloxy)phenyl)-3-(5-methylthiazol-2-yl)propanoate(4.63 g, 73.0%) as yellow oil.

¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (dd, J=9.1, 3.1 Hz, 1H), 7.37 (d, J=1.2Hz, 1H), 7.35 (d, J=3.1 Hz, 1H), 7.18 (d, J=9.2 Hz, 1H), 5.07 (dd,J=8.3, 7.1 Hz, 1H), 3.99 (q, J=7.1 Hz, 2H), 3.86 (s, 3H), 3.32 (dd,J=16.3, 6.9 Hz, 1H), 3.02 (dd, J=16.3, 6.9 Hz, 1H), 2.35 (d, J=1.0 Hz,3H), 1.08 (dd, J=9.2, 5.1 Hz, 3H).

Synthesis of Intermediate P43-(2-Methoxy-5-trifluoromethanesulfonyloxy-phenyl)-3-thiazol-2-yl-propionicacid ethyl ester

The synthesis is carried out as described for the synthesis ofintermediate P3 using 1,3-thiazole instead of 5-methyl-1,3-thiazole asstarting material.

Synthesis of Intermediate A13-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-propionic acid

(3-Bromo-5-chloro-phenyl)-(5-methyl-thiazol-2-yl)-methanone

To a stirring mixture of 5-methylthiazole (4.37 g, 44.1 mmol) in dry THF(30 L) under was added n-BuLi (44.1 mmol, 17.64 ml solution in hexanes)drop wise over 10 minutes at −78° C. under nitrogen atmosphere. Themixture was stirred between −78° C. and −60° C. for 30 minutes and thencooled to −78° C. A solution of 3-Bromo-5-chloro-benzoic acid methylester (11.0 g, 44.1 mmol) in THF (20 mL) was added drop wise over 10minutes. The resulting mixture was stirred at −78° C. for 30 minutes andwarmed to room temperature with stirring overnight. The mixture wascooled to 0° C. and treated with water (50 mL). The resulting mixturewas adjusted to pH around 6 with HCl (1N) and extracted with EtOAc (100mL×3). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography eluting with petroleum ether/EtOAc mixtures toafford (3-Bromo-5-chloro-phenyl)-(5-methyl-thiazol-2-yl)-methanone (14g, yield=100%) as a solid.

(Z)-3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-acrylic acidethyl ester

To

a suspension of NaH (60%, 1.77 g, 44.2 mmol) in dry THF (30 mL) wasadded ethyl 2-(diethoxyphosphoryl)acetate (10.12 g, 44.2 mmol) at −78°C. After being stirred at −78° C. for 1 hour, a solution of 14 g (44.2mmol) (3-Bromo-5-chloro-phenyl)-(5-methyl-thiazol-2-yl)-methanone in THF(10 mL) was added drop wise over 30 min. The mixture was stirred at −78°C. for 30 min and then warmed to room temperature with stirringovernight. The mixture was cooled to 0° C. and treated with water (50mL), pH value was adjusted to 6 with HCl (0.5 N) and extracted with EA(50 mL×3). The combined organic layers were dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bysilica gel chromatography eluting with petroleum ether/EtOAc mixtures toafford (Z)-3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-acrylicacid ethyl ester as an gel (18 g, yield=106%) The material is usedwithout further purification in the next step.

3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-propionic acidethyl ester

18 g (46.55 mmol) of(Z)-3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-acrylic acidethyl ester are dissolved in 250 ml Diethylether and 80 ml AcOH. 3 Eq(140 mmol) of zinc dust are added over a period of 60 minutes. Theresulting mixture is allowed to stir overnight, diluted with 100 mlEtOAc and filtrated over a pad of Celite. The solvent is removed invacuo, the residue taken up in EtOAc, washed with brine and dried overMgSO₄. After evaporation of the solvent 17 g (Yield=99%) of crudeproduct are obtained, which are used in the last step.

3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-propionic acid

17 g (43.73 mmol) of3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-propionic acidethyl ester are dissolved in 30 ml of a THF/MeOH/H2O=2:1:1 mixture andLiOH (2Eq) is added. After stirring overnight at RT, the solvent isremoved in vacuo and the crude material is treated with 30 ml of EtOAcand 30 ml of water with pH=4. The organic phase is separated, dried overNa2SO4 and the solvent removed in vacuo. The crude material isrecrystallized from heptane/EtOAc mixtures delivering 9.2 g (Yield=58%)of 3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-propionic acid.

According to the procedures described above the following additionalintermediates can be prepared:

A4: 3-(3-Bromo-5-fluoro-phenyl)-3-(5-methyl-thiazol-2-yl)-propionic acid

Using methyl-3-bromo-5-fluoro-benzoate as starting material.

A6: 3-(3-Bromo-phenyl)-3-(5-methyl-thiazol-2-yl)-propionic acid

Using methyl-benzoate as starting material

A7: 3-(3-Bromo-phenyl)-3-(4,5-dimethyl-thiazol-2-yl)-propionic acid

Using methyl-benzoate and 4,5-dimethyl-1,3-thiazole as startingmaterials

C2: 3-(3-Bromo-phenyl)-3-thiazol-2-yl-propionic acid

This material is commercially available from ZereneX (CAS-Number:1082829-38-6), but can be prepared accordingly starting frommethyl-benzoate and 1,3-thaizole as starting materials.

Synthesis of Intermediate A23-(3-Bromo-5-trifluoromethyl-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid

(3-Bromo-5-trifluoromethyl-phenyl)-(5-methyl-[1,3,4]oxadiazol-2-yl)-methanol

2.79 g (33.2 mmol) of 2-methyl-1,3,4-oxadiazole are dissolved in 45 mlTHF at −5° C., 33.2 mmol (25.54 ml) of isopropyl magnesiumchloride-lithium chloride complex are added during 20 minutes while thetemperature is kept <0° C. The mixture is kept at 0° C. for 30 minutes,then 0.8 Eq (6.7 g) of 3-Bromo-5-trifluoromethyl-benzaldehyde are addedand the resulting mixture is allowed to reach RT and stirred foradditional 60 minutes. The reaction is then stopped by the addition of10 ml saturated NH4Cl solution. 50 ml MTBE are added, the organic phaseis separated, washed with brine and dried over MgSO₄. The solvent isremoved in vacuo and the crude material (9 g) is used without furtherpurification in the next step:

(3-Bromo-5-trifluoromethyl-phenyl)-(5-methyl-[1,3,4]oxadiazol-2-yl)-methanone

The crude material from the first step is dissolved in 100 ml CH2Cl2 and20 g MnO2 are added. The resulting mixture is stirred for 60 minutes atRT and filtrated. After evaporation of the solvent 9.06 g (98%) of crudematerial is obtained, which is used without further purification in thenext step.

(Z)-3-(3-Bromo-5-trifluoromethyl-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-acrylicacid ethyl ester

To a suspension of NaH (60%, 1.13 g, 28.35 mmol) in dry THF (20 mL) wasadded ethyl 2-(diethoxyphosphoryl)acetate (6.49 g, 28.35 mmol) at −78°C. After being stirred at −78° C. for 1 hour, a solution of(3-Bromo-5-trifluoromethyl-phenyl)-(5-methyl-[1,3,4]oxadiazol-2-yl)-methanone(9.047 g, 27 mmol) in 20 ml THF was added drop wise over 30 min. Themixture was stirred at −78° C. for 30 min and then warmed to roomtemperature followed by stirring overnight. The mixture was cooled to 0°C. and treated with water (50 mL), pH value was adjusted to 6 with HCl(0.5 N) and extracted with EtOAc (50 mL×3). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith a petroleum ether/EtOAc mixture to afford 9 g of the desiredproduct (Yield: 90%).

Synthesis of3-(3-Bromo-5-trifluoromethyl-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid ethyl ester

11.2 g (27.64 mmol)(Z)-3-(3-Bromo-5-trifluoromethyl-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-acrylicacid ethyl ester is dissolved in 200 ml acetic acid and 14.1 g Zinc dust(215.6 mmol, 7.8 mmol) is added slowly over a period of 30 minutes. Thetemperature of the reaction mixture is not allowed to reach >30° C.during the addition of the zinc dust. The resulting mixture is allowedto stir overnight. After filtration 200 ml EtOAc and 200 ml water areadded and the organic phase is separated and washed with brine. Afterremoval of the solvent the crude material is purified by columnchromatography on silica gel using heptane/EtOAc=3:1 as eluent. 3.97 gof3-(3-Bromo-5-trifluoromethyl-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid ethyl ester (yield=35%) are isolated.

Synthesis of3-(3-Bromo-5-trifluoromethyl-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid

3.97 g (9.75 mmol) of3-(3-Bromo-5-trifluoromethyl-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid ethyl ester are dissolved in 10 ml ethanol and 6.34 ml of a 2N NaOHsolution are added. The mixture is allowed to stir for 4 hours at RT,the ethanol is removed and the residue taken up in 30 ml EtOAc and 20 mlwater.

After phase separation the organic phase is dried over Mg2SO4 and thesolvent removed in vacuo to deliver 3.3 g (Yield=89%) of the desiredproduct3-(3-Bromo-5-trifluoro-methyl-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid.

According to the procedure described above the following additionalintermediates are prepared:

A8:3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid

Using 3-bromo-5-chloro-benzaldehyde as starting material

A9:3-(3-Bromo-5-fluoro-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid

Using 3-Bromo-5-fluoro-benzaldehyde as starting material

A10:3-(5-Bromo-pyridin-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid

Using 5-bromo-nicotinaldehyde as starting material

C1: 3-(3-Bromo-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid

This intermediate is commercially available from Aurora Building Blocks(CAS-Number: 1082916-80-0), but can be obtained using3-bromo-benzaldehyde

Synthesis of Intermediate A33-(3-Bromo-5-fluoro-phenyl)-3-oxazol-2-yl-propionic acid

Synthesis of 3-Bromo-5-fluoro-benzoyl chloride

10 g of 3-bromo-5-fluoro-benzoic acid are suspended in 100 ml of DCM,0.5 ml DMF and 4.5 ml oxalyl chloride (1.15 Eq) are added and theresulting mixture is stirred for 100 minutes at RT. The solvent isremoved by vacuo and the benzoic acid chloride is isolated bydistillation.

Synthesis of (3-Bromo-5-fluoro-phenyl)-oxazol-2-yl-methanone

To a stirring mixture of 1,3-oxazole (3.46 g, 50 mmol) in dry THF (50mL) was added n-BuLi (1.1 Eq, 20.01 ml solution in hexanes) drop wiseover 10 minutes at −78° C. under nitrogen atmosphere. After stirring for30 minutes at −78° C. zinc chloride (0.1 mmol, 2.2Eq) as a 2M solutionin 5-methyl-tetrahydrofurane was added within 30 minutes and the mixturewas allowed to reach −20° C. during the addition. Then the mixture wasstirred at 0° C. for 40 minutes, CuI (8.66 g, 45.5 mmol) was added andstirring continued for additional 10 minutes. 3-Bromo-5-fluoro-benzoylchloride (45.5 mmol, 8.66 g) was dissolved in 50 ml of THF and added tothe metallated 1,3-oxazole. Stirring was continued until completeconversion was observed by LCMS and 50 ml water and 50 ml of a 0.5 Mcitric acid solution were added. The solid material from the reactionmixture was filtered off and washed with 5-methyl-thf. The organic phasewas separated, washed with brine and dried over MgSO4. 10.8 g of crudematerial (yield=88%) were obtained and used directly in the next step.

The mixture was stirred between −78° C. and −60° C. for 30 minutes andthen cooled to −78° C. A solution of 3-Bromo-5-chloro-benzoic acidmethyl ester (11.0 g, 44.1 mmol) in THF (20 mL) was added drop wise over10 minutes. The resulting mixture was stirred at −78° C. for 30 minutesand warmed to room temperature with stirring overnight. The mixture wascooled to 0° C. and treated with water (50 mL). The resulting mixturewas adjusted to pH around 6 with HCl (1N) and extracted with EtOAc (100mL×3). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography eluting with petroleum ether/EtOAc mixtures toafford (3-Bromo-5-chloro-phenyl)-(5-methyl-thiazol-2-yl)-methanone (14g, yield=100%) as a solid.

Synthesis of (Z)-3-(3-Bromo-5-fluoro-phenyl)-3-oxazol-2-yl-acrylic acidethyl ester

To a suspension of NaH (60%, 1.6 g, 40 mmol) in dry THF (30 mL) wasadded ethyl 2-(diethoxyphosphoryl)acetate (9.15 g, 40 mmol) at −78° C.After being stirred at −78° C. for 1 hour, a solution of(3-Bromo-5-fluoro-phenyl)-oxazol-2-yl-methanone (10.8 g, 40 mmol) in 20ml THF was added drop wise over 30 min. The mixture was stirred at −78°C. for 30 min and then warmed to room temperature followed by stirringovernight. The mixture was cooled to 0° C. and treated with water (50mL), pH value was adjusted to 6 with HCl (0.5 N) and extracted withEtOAc (50 mL×3). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with a petroleumether/EtOAc mixture to afford 9.5 g of the desired product (Yield: 61%)

Synthesis of 3-(3-Bromo-5-fluoro-phenyl)-3-oxazol-2-yl-propionic acidethyl ester

9.5 g (27.93 mmol) (Z)-3-(3-Bromo-5-fluoro-phenyl)-3-oxazol-2-yl-acrylicacid ethyl ester is dissolved in 200 ml acetic acid and 9.5 g Zinc dust(11 Ea)) is added slowly over a period of 30 minutes. The temperature ofthe reaction mixture is not allowed to reach >30° C. during the additionof the zinc dust. The resulting mixture is allowed to stir overnight.After filtration 200 ml EtOAc and 200 ml water are added and the organicphase is separated and washed with brine. After removal of the solventthe crude material is purified by column chromatography on silica gelusing heptane/EtOAc=3:1 as eluent. 9.50 g of3-(3-Bromo-5-fluoro-phenyl)-3-oxazol-2-yl-propionic acid ethyl ester areisolated (yield=615)

Synthesis of 3-(3-Bromo-5-fluoro-phenyl)-3-oxazol-2-yl-propionic acid

9.50 g (27.76 mmolmmol) of3-(3-Bromo-5-fluoro-phenyl)-3-oxazol-2-yl-propionic acid ethyl ester aredissolved in 30 ml ethanol and 20.82 ml of a 2N NaOH solution are added.The mixture is allowed to stir for 4 hours at RT, the ethanol is removedand the residue taken up in 30 ml EtOAc and 20 ml water. After phaseseparation the organic phase is dried over Mg2SO4 and the solventremoved in vacuo to deliver 8.35 g (Yield=58%) of the desired product3-(3-Bromo-5-fluoro-phenyl)-3-oxazol-2-yl-propionic acid.

According to this procedure the following additional intermediates areprepared:

A5: 3-(3-Bromo-5-fluoro-phenyl)-3-oxazol-2-yl-propionic acid

Using 3-bromo benzoyl-chloride as starting material

Synthesis of Novel Boronic Acids6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-ylboronic acid

Methyl 2-(3-methoxyphenoxy)acetate

To a mixture of 3-methoxyphenol (20 g, 161.3 mmol) and Cs₂CO₃ (52.4 g,161.3 mmol) in DMF (200 mL), methyl bromoacetate (24.5 g, 161.3 mmol)was added. The reaction mixture was stirred at room temperature underargon overnight. The inorganic precipitate was filtered off, and thefiltrate was concentrated under reduced pressure. The residue waspartitioned between water (200 mL) and CH₂Cl₂ (200 mL×3). The combinedorganic solution was dried over Na₂SO₄ and evaporated to give (28 g,90%) product.

1-(3-methoxyphenoxy)-2-methylpropan-2-ol

To a solution of methyl 2-(3-methoxyphenoxy)acetate (28 g, 143 mmol) inether (200 mL) cooled in an ice water bath was added drop wise asolution of methyl magnesium bromide (143 mmol, 3M in ether) in ether.After 1 h the reaction mixture was poured into 500 mL of 2N HCl. Themixture was extracted with EA (200 mL×3). The combined organic layerswere dried over Na₂SO₄. After filtration and evaporation of the solvent,the intermediate (25 g 90%) was obtained.

6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran

To a solution of phosphorous pentoxide (55.1 g, 383 mmol) inmethanesulfonic acid (100 mL) was added drop wise1-(3-methoxyphenoxy)-2-methylpropan-2-ol (25 g, 127.6 mmol) over a 30min period. The reaction mixture was stirred for 3 h at r.t. Thereaction mixture was poured into 500 mL of ice water and extracted withether (200 mL×3). The combined extracts were dried and evaporated. Theresidue was purified by silica gel column chromatography eluting withpetroleum ether/ether (9:1) to afford6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran (5.5 g, 25%) as a yellowoil.

6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-ylboronic acid

s-BuLi (35 mL, 1.3M in cyclohexane) was added to TMEDA (6.6 mL) at −78°C. drop wise within 30 min, 20 mL of THF was added to keep stirring.After 20 min, 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran (5.4 g, 30.3mmol) in THF (30 mL) was added into the lithium solution slowly. Thesolution was stirred at −78° C. for 1.5 h and trimethyl borate (18 mL)was added. The mixture was warmed to room temperature and stirred atroom temperature overnight. The solution was acidified to pH=5-6 andextracted with ethyl acetate. The organic layer was concentrated and theresulted residue was purified on column chromatography (silica gel,dichloromethane/petroleum ether=3/1) to give the crude product, whichwas sonicated with petroleum ether. The white precipitate was filteredand dried to give6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-ylboronic acid (3.55 g,53%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (brs, 2H), 7.07 (d, J=8.0 Hz, 1H), 6.36(d, J=8.4 Hz, 1H), 3.68 (s, 3H), 2.87 (s, 2H), 1.38 (s, 6H).

2-(2-methoxy-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

2-bromo-4-(methylsulfonyl)phenol

To a solution of 4-(methylsulfonyl)phenol (5 g, 29.1 mmol) in ether (100mL) at −15° C. was slowly added acetic acid (5 mL). To this coldsolution was slowly added Br₂ (5.1 g, 32.0 mmol) and the reaction wasstirred at −10° C. for 1 h and then warmed to r.t. and stirred forfurther 10 h. After the reaction was completed, 100 mL of sat. NaHCO₃aq. was added and the mixture was extracted with EA (50 mL×3). Thecombined organic layers were washed with brine and dried over Na₂SO₄.After filtration and evaporation of the solvent,2-bromo-4-(methylsulfonyl)phenol (3.2 g, 43.6%) was obtained as a whitesolid.

2-bromo-1-methoxy-4-(methylsulfonyl)benzene

To a solution of 2-bromo-4-(methylsulfonyl) phenol (3.2 g, 12.7 mmol) inDMF (35 mL) at 0° C. was added K₂CO₃ (5.3 g, 38.1 mmol). The reactionwas stirred at 0° C. for 0.5 h and to this cold solution was slowlyadded CH₃I (2.7 g, 19.1 mmol) drop wise. The reaction was stirred atr.t. overnight. After the reaction was completed, 80 mL of ice-water wasadded. The mixture was extracted with EA (60 mL×3). The combined organiclayers were washed with brine and dried over Na₂SO₄. After filtrationand evaporation of the solvent, the obtained residue was purified oncolumn chromatography (silica gel, ethyl acetate/petroleum ether=1:4) togive 2-bromo-1-methoxy-4-(methylsulfonyl)benzene (2.12 g, 63.0%) asyellow solid.

2-(2-methoxy-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 2-bromo-1-methoxy-4-(methylsulfonyl)benzene (2.12 g, 8mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.65g, 10.4 mmol), potassium acetate (2.4 g, 24 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (600 mg) in1,4-dioxane (50 mL) were heated to 80° C. overnight. After cooling, themixture was filtered. The filtrate was concentrated and the resultedresidue was purified on column chromatography (silica gel,dichloromethane/petroleum ether=3/1) to give2-(2-methoxy-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(200 mg, 8%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.01-7.98 (m, 2H), 7.21 (d, J=8.8 Hz, 1H),3.85 (s, 3H), 3.15 (s, 3H), 1.32 (s, 12H).

2-methoxy-6-(pyrrolidine-1-carbonyl)phenylboronic acid

(3-methoxyphenyl)(pyrrolidin-1-yl)methanone

A solution of 3-methoxybenzoic acid (13.5 g, 88.8 mmol), pyrrolidine (9mL, 133 mmol), HATU (33 g, 88.8 mmol) and DIEA (30 mL, 172 mmol) in DMF(100 mL) was stirred at room temperature for 2 h. The solution was addedwater and extracted with ethyl acetate (200 mL×3). The organic layer wasdried and concentrated. The residue was purified by silica gelchromatography (eluted with petroleum ether:ethyl acetate=2:1 to 1:1) togive (3-methoxyphenyl)(pyrrolidin-1-yl)methanone (23 g, 100%) as ayellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.26 (m, 1H), 7.05 (m, 2H), 6.94-6.92 (m,1H), 3.80 (s, 3H), 3.59 (t, J=6.8 Hz, 2H), 3.40 (t, J=6.8 Hz, 2H),1.94-1.83 (m, 4H).

2-methoxy-6-(pyrrolidine-1-carbonyl)phenylboronic acid

s-BuLi (70 mL, 1.3M in cyclohexane) was added to TMEDA (15.3 g, 131.9mmol) at −78° C. dropwise within 30 min. After stirring for 20 min,(3-methoxyphenyl)(pyrrolidin-1-yl)methanone (16 g, 78 mmol) in THF (40mL) was added into the lithium solution slowly. The solution was stirredat −78° C. for 1.5 h and trimethyl borate (36 mL, 322.6 mmol) was added.The mixture was warmed to room temperature and stirred at rt overnight.The solution was acidified to pH=5-6 and the precipitate were filtered.The filter cake was washed with water and ethyl acetate to give2-methoxy-6-(pyrrolidine-1-carbonyl)phenylboronic acid (5.5 g, 28%) as awhite solid.

¹H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J=8.0 Hz, 1H), 7.38 (t, J=8.0 Hz,1H), 7.12 (d, J=8.0 Hz, 1H0, 7.01 (brs, 2H), 4.08 (t, J=6.0 Hz, 2H),3.84-3.74 (m, 5H), 2.11-2.07 (m, 2H), 1.94-1.91 (m, 2H).

Synthesis of(S)-3-(5′-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid and(R)-3-(5-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid

12.83 g (66.11 mmol) of 5-isopropyl-2-methoxybenzeneboronic acid, 48.97g (150.3 mmol) and 18.7 g (60.1 mmol) of3-(3-Bromo-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid areheated together with 3 mmol of bis(triphenylphosphine)palladium (II)dichloride in 200 ml of DMF and 30 ml of water for 10 hours at 100° C.The reaction mixture is diluted with conc. NH4Cl solution (200 ml) andextracted with methyl-tetrahydrofurane. The organic phase is filtratedover Celite and 100 g of SiO2 and the solvent is removed in vacuo. Theobtained crude3-(5′-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid is used directly in the next step. (Yield=57%, 28 g)

The racemic3-(5′-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid is subjected to chromatography on a chiral column using aheptane-methanol gradient to isolate the pure enantiomers(S)-3-(5′-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid and(R)-3-(5′-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid. The configuration on the chiral carbon atom is arbitrarilyassigned (S) to the enantiomer with the shortest retention time on theapplied chiral column and (R) to the enantiomer with the longestretention time on the applied chiral column.

Analogously as described in the synthesis examples, the examplecompounds of the formula I listed in Table 1 were prepared.

TABLE 1 Example compounds of the formula I CATHA St. Suzuki IC50 Obs. RtNo. CHEMICAL_NAME mat reaction [μM] Mass [min] LC/MS 13-(3′-tert-Butyl-biphenyl-3- C2 A 1.89 366.14 4.88 LC3yl)-3-thiazol-2-yl-propionic acid 2 3-(3-Bromo-phenyl)-3- A7 A 7.78340.04 1.89 LC1 (4,5-dimethyl-thiazol-2-yl)- propionic acid 33-(3′-Methyl-biphenyl-3- C2 A 0.784 322.15 1.81 LC1yl)-3-thiazol-2-yl-propionic acid 4 3-(2′-Chloro-3′-methyl- C2 A 0.797356.2 1.86 LC1 biphenyl-3-yl)-3-thiazol-2- yl-propionic acid 53-(3′-Chloro-biphenyl-3- C2 A 0.967 342.09 1.83 LC1yl)-3-thiazol-2-yl-propionic acid 6 3-(3′-Chloro-2′-methyl- C2 A 1.668356.16 1.9 LC1 biphenyl-3-yl)-3-thiazol-2- yl-propionic acid 73-(4′-Chloro-biphenyl-3- C2 A 1.749 342.12 1.84 LC1yl)-3-thiazol-2-yl-propionic acid 8 3-(2′-Chloro-biphenyl-3- C2 A 2.040342.14 1.78 LC1 yl)-3-thiazol-2-yl-propionic acid 93-(2′,3′-Dimethyl-biphenyl- C2 A 2.483 336.16 1.86 LC13-yl)-3-thiazol-2-yl- propionic acid 10 3-Biphenyl-3-yl-3-thiazol- C2 A2.586 310.21 1.74 LC1 2-yl-propionic acid 11 3-(2′-Chloro-3′-fluoro- C2A 2.720 360.14 1.79 LC1 biphenyl-3-yl)-3-thiazol-2- yl-propionic acid 123-(2′-Methyl-biphenyl-3- C2 A 3.539 322.14 1.8 LC1yl)-3-thiazol-2-yl-propionic acid 13 3-(2′-Fluoro-5′- C2 A 3.619 394.21.85 LC1 trifluoromethyl-biphenyl-3- yl)-3-thiazol-2-yl-propionic acid14 3-(4′-Fluoro-biphenyl-3-yl)- C2 A 4.304 326.09 1.76 LC13-thiazol-2-yl-propionic acid 15 3-(2′,3′-Dichloro-biphenyl- C1 A 0.634375.08 1.76 LC1 3-yl)-3-(5-methyl- [1,3,4]oxadiazol-2-yl)- propionicacid 16 3-(5-Methyl- C1 A 23.2 310.16 0.77 LC1[1,3,4]oxadiazol-2-yl)-3-(3- pyridin-4-yl-phenyl)- propionic acid;compound with trifluoro-acetic acid 17 3-(2′-Fluoro-3′-methoxy- C2 A0.588 358.17 1.71 LC1 biphenyl-3-yl)-3-thiazol-2- yl-propionic acid 183-[3-(1-Methyl-1H-indazol- C2 A 0.769 364.19 1.69 LC13-yl)-phenyl]-3-thiazol-2- yl-propionic acid; compound with trifluoro-acetic acid 19 3-[3-(2,3-Dihydro- C2 A 0.987 368.18 1.7 LC1benzo[1,4]dioxin-6-yl)- phenyl]-3-thiazol-2-yl- propionic acid 203-(2′-Fluoro-5′-propoxy- C2 A 1.11 386.21 1.9 LC1biphenyl-3-yl)-3-thiazol-2- yl-propionic acid 213-(3′-Methoxy-biphenyl-3- C2 A 1.179 340.2 1.74 LC1yl)-3-thiazol-2-yl-propionic acid 22 3-(2′,5′-Difluoro-4′- C2 A 1.32376.14 1.75 LC1 methoxy-biphenyl-3-yl)-3- thiazol-2-yl-propionic acid 233-[3-(6-Amino-2-fluoro- C2 A 1.39 344.18 1.44 LC1pyridin-3-yl)-phenyl]-3- thiazol-2-yl-propionic acid; compound withtrifluoro- acetic acid 24 3-(3′-Ethoxy-biphenyl-3- C2 A 1.499 354.2 1.81LC1 yl)-3-thiazol-2-yl-propionic acid 25 3-(4′-Methoxy-3′,5′- C2 A 1.651368.2 1.84 LC1 dimethyl-biphenyl-3-yl)-3- thiazol-2-yl-propionic acid 263-(3′-Propoxy-biphenyl-3- C2 A 1.67 368.22 1.9 LC1yl)-3-thiazol-2-yl-propionic acid 27 3-(3′-Cyanomethoxy- C2 A 1.94365.18 1.67 LC1 biphenyl-3-yl)-3-thiazol-2- yl-propionic acid 283-Thiazol-2-yl-3-(3′- C2 A 2.25 394.14 1.89 LC1trifluoromethoxy-biphenyl- 3-yl)-propionic acid 293-(4′-Hydroxy-3′-methoxy- C2 A 2.28 356.17 1.54 LC1biphenyl-3-yl)-3-thiazol-2- yl-propionic acid 303-(4′-Cyclopropylmethoxy- C2 A 2.29 380.2 1.87 LC1biphenyl-3-yl)-3-thiazol-2- yl-propionic acid 313-(5′-Fluoro-3′-isobutoxy- C2 A 2.31 400.23 2 LC1biphenyl-3-yl)-3-thiazol-2- yl-propionic acid 32 3-(4′-Cyanomethoxy- C2A 2.42 365.15 1.65 LC1 biphenyl-3-yl)-3-thiazol-2- yl-propionic acid 333-(4′-Benzyloxy-3′-fluoro- C2 A 2.426 434.2 1.94 LC1biphenyl-3-yl)-3-thiazol-2- yl-propionic acid 343-Thiazol-2-yl-3-[3′-(2,2,2- C2 A 2.46 408.16 1.84 LC1trifluoro-ethoxy)-biphenyl- 3-yl]-propionic acid 353-(3′-Benzyloxy-biphenyl- C2 A 2.772 416.24 1.93 LC13-yl)-3-thiazol-2-yl- propionic acid 36 3-(4′-Isobutoxy-biphenyl- C2 A2.810 382.21 1.97 LC1 3-yl)-3-thiazol-2-yl- propionic acid 373-(2′-Formyl-5′-methoxy- C2 A 3.202 368.18 1.65 LC1biphenyl-3-yl)-3-thiazol-2- yl-propionic acid 383-(3′-Benzyloxy-4′-chloro- C2 A 7.87 450.16 1.99 LC1biphenyl-3-yl)-3-thiazol-2- yl-propionic acid 393-[3-(6-Methoxy-pyridin-3- C2 A 8.35 341.18 1.62 LC1yl)-phenyl]-3-thiazol-2-yl- propionic acid 40 3-[3-(2 ,5-Dimethyl-2H- C2A 9.54 328.18 1.48 LC1 pyrazol-3-yl)-phenyl]-3- thiazol-2-yl-propionicacid; compound with trifluoro- acetic acid 41 3-[3-(2-Chloro-pyridin-3-C2 A 11.60 345.11 1.55 LC1 yl)-phenyl]-3-thiazol-2-yl- propionic acid 423-[3-(2-Methyl-2H-pyrazol- C2 A 15.1 314.17 1.42 LC13-yl)-phenyl]-3-thiazol-2- yl-propionic acid; compound with trifluoro-acetic acid 43 3-[3-(3-Chloro-pyridin-4- C2 A 19.44 345.12 1.54 LC1yl)-phenyl]-3-thiazol-2-yl- propionic acid 44 3-(3-Pyridin-3-yl-phenyl)-C2 A 21.19 311.19 1.1 LC1 3-thiazol-2-yl-propionic acid 453-[3-(6-Cyano-pyridin-3- C2 A 22.58 336.16 1.53 LC1yl)-phenyl]-3-thiazol-2-yl- propionic acid 46 3-[3-(2-Fluoro-pyridin-4-C2 A 23.6 329.15 1.56 LC1 yl)-phenyl]-3-thiazol-2-yl- propionic acid 473-[3-(3-Fluoro-pyridin-4- C2 A 24.8 329.14 1.46 LC1yl)-phenyl]-3-thiazol-2-yl- propionic acid 48 3-(3-Pyridin-4-yl-phenyl)-C2 A 311.19 1 LC1 3-thiazol-2-yl-propionic acid; compound withtrifluoro-acetic acid 49 3-{3-[5-(Morpholine-4- C2 A 424.17 1.32 LC1carbonyl)-pyridin-3-yl]- phenyl}-3-thiazol-2-yl- propionic acid 503-(5′-Chloro-2′-fluoro- A6 A 0.228 376.17 1.88 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 513-(2′-Fluoro-3′-methoxy- A6 A 0.397 372.21 1.77 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 523-(2′,5′-Difluoro-4′- A6 A 0.466 390.25 1.8 LC1methoxy-biphenyl-3-yl)-3- (5-methyl-thiazol-2-yl)- propionic acid 533-(2′-Fluoro-biphenyl-3-yl)- A6 A 0.631 342.21 1.8 LC13-(5-methyl-thiazol-2-yl)- propionic acid 54 3-(2′-Fluoro-4′-methoxy- A6A 0.989 372.23 1.8 LC1 biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionic acid 55 3-(2′-Acetyl-biphenyl-3-yl)- A6 A 2.303366.23 1.69 LC1 3-(5-methyl-thiazol-2-yl)- propionic acid 563-(2′-Carbamoyl-biphenyl- A6 A 5.384 367.23 1.45 LC13-yl)-3-(5-methyl-thiazol-2- yl)-propionic acid 573-[3-(3-Fluoro-pyridin-4- A6 A 7.06 343.19 1.55 LC1yl)-phenyl[-3-(5-methyl- thiazol-2-yl)-propionic acid 583-(5-Methyl-thiazol-2-yl)-3- A6 A 7.535 325.21 1.25 LC1(3-pyridin-3-yl-phenyl)- propionic acid 59 3-(5-Methyl-thiazol-2-yl)-3-A6 A 13.59 436.26 1.41 LC1 {3-[5-(morpholine-4- carbonyl)-pyridin-3-yl]-phenyl}-propionic acid 60 3-(5-Methyl-thiazol-2-yl)-3- A6 A 13.74 325.21.13 LC1 (3-pyridin-4-yl-phenyl)- propionic acid 613-(3′-Chloro-2′-fluoro-4- P3 B 0.954 406.12 1.87 LC1methoxy-biphenyl-3-yl)-3- (5-methyl-thiazol-2-yl)- propionic acid 623-(2′-Fluoro-4-methoxy-4′- P3 B 0.97 386.18 1.86 LC1methyl-biphenyl-3-yl)-3-(5- methyl-thiazol-2-yl)- propionic acid 633-(2′,5′-Difluoro-4- P3 B 0.975 390.15 1.81 LC1methoxy-biphenyl-3-yl)-3- (5-methyl-thiazol-2-yl)- propionic acid 643-(5′-Fluoro-4-methoxy-2′- P3 B 1.2 386.15 1.86 LC1methyl-biphenyl-3-yl)-3-(5- methyl-thiazol-2-yl)- propionic acid 653-(5′-Chloro-2′-fluoro-4- P3 B 1.23 406.1 1.88 LC1methoxy-biphenyl-3-yl)-3- (5-methyl-thiazol-2-yl)- propionic acid 663-(2′-Chloro-5′-fluoro-4- P3 B 1.25 406.12 1.85 LC1methoxy-biphenyl-3-yl)-3- (5-methyl-thiazol-2-yl)- propionic acid 673-(3′-Chloro-4-methoxy-2′- P3 B 1.31 402.15 1.94 LC1methyl-biphenyl-3-yl)-3-(5- methyl-thiazol-2-yl)- propionic acid 683-(4-Methoxy-4′-methyl- P3 B 1.59 368.17 1.86 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 693-(2′,3′-Difluoro-4- P3 B 1.77 390.14 1.81 LC1 methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)- propionic acid 70 3-(3′-Fluoro-4-methoxy- P3 B1.96 372.14 1.81 LC1 biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionicacid 71 3-(4-Methoxy-2′,3′- P3 B 2.3 382.19 1.91 LC1dimethyl-biphenyl-3-yl)-3- (5-methyl-thiazol-2-yl)- propionic acid 723-(2′-Fluoro-4-methoxy- P3 B 2.34 372.16 1.79 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 733-(2′-Fluoro-4-methoxy-3′- P3 B 2.42 386.15 1.86 LC1methyl-biphenyl-3-yl)-3-(5- methyl-thiazol-2-yl)- propionic acid 743-(2′,4′-Difluoro-4- P3 B 2.65 390.13 1.82 LC1 methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)- propionic acid 75 3-(4-Methoxy-2′,4′- P3 B 3.09382.21 1.92 LC1 dimethyl-biphenyl-3-yl)-3- (5-methyl-thiazol-2-yl)-propionic acid 76 3-(4′-Chloro-4-methoxy- P3 B 3.2 388.12 1.88 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 773-(2′-Fluoro-4,4′- P3 B 3.27 402.18 1.8 LC1 dimethoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)- propionic acid 78 3-(4-Methoxy-2′-methyl- P3B 3.28 368.17 1.85 LC1 biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionic acid 79 3-(4′-Chloro-2′-fluoro-4- P3 B 3.57406.11 1.9 LC1 methoxy-biphenyl-3-yl)-3- (5-methyl-thiazol-2-yl)-propionic acid 80 3-(4′-Fluoro-4-methoxy-2′- P3 B 3.73 386.16 1.86 LC1methyl-biphenyl-3-yl)-3-(5- methyl-thiazol-2-yl)- propionic acid 813-(3′-Chloro-4-methoxy- P3 B 3.74 388.1 1.88 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 823-(2′-Chloro-3′-fluoro-4- P3 B 4.01 406.1 1.84 LC1methoxy-biphenyl-3-yl)-3- (5-methyl-thiazol-2-yl)- propionic acid 833-(4-Methoxy-4′- P3 B 4.38 422.15 1.9 LC1 trifluoromethyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2- yl)-propionic acid 84 3-(4′-Fluoro-4-methoxy-P3 B 4.39 372.16 1.8 LC1 biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionic acid 85 3-(4,3′-Dimethoxy- P3 B 5.56 384.17 1.78LC1 biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 863-(2′-Fluoro-4-methoxy-5′- P3 B 5.68 386.18 1.86 LC1methyl-biphenyl-3-yl)-3-(5- methyl-thiazol-2-yl)- propionic acid 873-(2′-Chloro-4′-fluoro-4- P3 B 6.36 406.13 1.86 LC1methoxy-biphenyl-3-yl)-3- (5-methyl-thiazol-2-yl)- propionic acid 883-(2′-Chloro-4-methoxy- P3 B 6.69 388.12 1.84 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 893-(4-Methoxy-4′- P3 B 6.73 438.15 1.93 LC1 trifluoromethoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2- yl)-propionic acid 903-(4-Methoxy-3′-methyl- P3 B 7.12 368.16 1.86 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 913-(4-Methoxy-3′- P3 B 7.77 422.15 1.9 LC1 trifluoromethyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2- yl)-propionic acid 92 3-(4,4′-Dimethoxy- P3 B7.81 384.16 1.77 LC1 biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionicacid 93 3-(4′-Cyano-4-methoxy- P3 B 8.8 379.15 1.71 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 943-(3′-Cyano-4-methoxy- P3 B 9.26 379.16 1.72 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 953-(4-Methoxy-2′- P3 B 10.2 422.16 1.86 LC1 trifluoromethyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2- yl)-propionic acid 96 3-(4-Methoxy-3′- P3 B18.1 438.15 1.92 LC1 trifluoromethoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2- yl)-propionic acid 97 3-(2′-Carbamoyl-4- P3B 19.3 397.16 1.46 LC1 methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)- propionic acid 98 3-(2-Methoxy-5-pyridin-4- P3B 355.15 1.16 LC1 yl-phenyl)-3-(5-methyl- thiazol-2-yl)-propionic acid99 3-(2-Methoxy-5-pyridin-3- P3 B 355.13 1.24 LC1yl-phenyl)-3-(5-methyl- thiazol-2-yl)-propionic acid 1003-[5-(3-Fluoro-pyridin-4- P3 B 373.13 1.53 LC1 yl)-2-methoxy-phenyl]-3-(5-methyl-thiazol-2-yl)- propionic acid 101 3-(5-Chloro-2′,5′-difluoro-A1 A 0.136 394.14 1.91 LC1 biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionic acid 102 3-(5-Chloro-2′-fluoro-3′- A1 A 0.184390.18 1.97 LC1 methyl-biphenyl-3-yl)-3-(5- methyl-thiazol-2-yl)-propionic acid 103 3-(5,3′-Dichloro-2′-fluoro- A1 A 0.197 410.11 1.97LC1 biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 1043-(5-Chloro-2′- A1 A 0.221 442.15 1.96 LC1 trifluoromethoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2- yl)-propionic acid 1053-(5-Chloro-2′-fluoro-5′- A1 A 0.232 390.16 1.96 LC1methyl-biphenyl-3-yl)-3-(5- methyl-thiazol-2-yl)- propionic acid 1063-(2′-Acetyl-5-chloro- A1 A 0.25 400.19 1.8 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 1073-(5-Chloro-2′-fluoro- A1 A 0.328 376.16 1.9 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 1083-(5-Chloro-2′,6′-difluoro- A1 A 0.335 424.71 1.91 LC14′-methoxy-biphenyl-3-yl)- 3-(5-methyl-thiazol-2-yl)- propionic acid 1093-(5-Chloro-2′,3′-difluoro- A1 A 0.354 394.14 1.91 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 1103-(2′-Carbamoyl-5-chloro- A1 A 0.404 401.17 1.58 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 1113-(5-Chloro-3′- A1 A 0.406 442.15 2.01 LC1 trifluoromethoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2- yl)-propionic acid 1123-(3-Chloro-5-pyridin-4-yl- A1 A 0.459 359.14 1.36 LC1phenyl)-3-(5-methyl- thiazol-2-yl)-propionic acid; compound withtrifluoro-acetic acid 113 3-(5-Chloro-2′-fluoro-4′- A1 A 0.563 406.181.9 LC1 methoxy-biphenyl-3-yl)-3- (5-methyl-thiazol-2-yl)- propionicacid 114 3-(5-Chloro-2′-cyano- A1 A 0.567 383.16 1.79 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 1153-(3-Chloro-5-pyridin-3-yl- A1 A 1.06 359.15 1.48 LC1phenyl)-3-(5-methyl- thiazol-2-yl)-propionic acid; compound withtrifluoro-acetic acid 116 3-(5-Chloro-2′- A1 A 1.44 429.23 1.69 LC1dimethylcarbamoyl- biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionicacid 117 3-[3-Chloro-5-(3-fluoro- A1 A 1.56 377.14 1.69 LC1pyridin-4-yl)-phenyl]-3-(5- methyl-thiazol-2-yl)- propionic acid 1183-(5,2′-Difluoro-5′-methyl- A3 A 0.437 374.19 1.9 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 1193-(5,2′-Difluoro-3′-methyl- A3 A 0.488 344.15 1.8 LC1biphenyl-3-yl)-3-oxazol-2- yl-propionic acid 1203-(5-Methyl-thiazol-2-yl)-3- A3 A 0.649 378.14 1.84 LC1(5,2′,5′-trifluoro-biphenyl- 3-yl)-propionic acid 1213-(2′-Acetyl-5-fluoro- A3 A 0.707 384.18 1.73 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 1223-(5,2′-Difluoro-biphenyl- A3 A 0.78 360.15 1.83 LC13-yl)-3-(5-methyl-thiazol-2- yl)-propionic acid 1233-(5,2′-Difluoro-5′-methyl- A3 A 0.903 344.14 1.79 LC1biphenyl-3-yl)-3-oxazol-2- yl-propionic acid 124 3-(5-Fluoro-3′- A3 A0.975 426.2 1.95 LC1 trifluoromethoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2- yl)-propionic acid 1253-(5,2′-Difluoro-4′-methyl- A3 A 1.16 344.14 1.8 LC1biphenyl-3-yl)-3-oxazol-2- yl-propionic acid 1263-Oxazol-2-yl-3-(5,2′,6′- A3 A 1.22 378.13 1.74 LC1trifluoro-4′-methoxy- biphenyl-3-yl)-propionic acid 1273-(2′-Carbamoyl-5-fluoro- A3 A 1.23 385.19 1.5 LC1biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionic acid 1283-(3-Fluoro-5-pyridin-3-yl- A3 A 1.33 343.16 1.38 LC1phenyl)-3-(5-methyl- thiazol-2-yl)-propionic acid; compound withtrifluoro-acetic acid 129 3-Oxazol-2-yl-3-(5,2′,3′- A3 A 1.45 348.121.74 LC1 trifluoro-biphenyl-3-yl)- propionic acid 1303-Oxazol-2-yl-3-(5,2′,5′- A3 A 1.49 348.11 1.73 LC1trifluoro-biphenyl-3-yl)- propionic acid 131 3-(2′-Cyano-5-fluoro- A3 A1.69 367.16 1.72 LC1 biphenyl-3-yl)-3-(5-methyl- thiazol-2-yl)-propionicacid 132 3-(2′-Dimethylcarbamoyl- A3 A 1.7 413.24 1.63 LC15-fluoro-biphenyl-3-yl)-3- (5-methyl-thiazol-2-yl)- propionic acid 1333-(5,2′-Difluoro-biphenyl- A3 A 1.72 330.13 1.71 LC13-yl)-3-oxazol-2-yl- propionic acid 134 3-(2′-Carbamoyl-5-fluoro- A3 A1.77 355.18 1.35 LC1 biphenyl-3-yl)-3-oxazol-2- yl-propionic acid 1353-(5,2′-Difluoro-4′- A3 A 2.02 360.13 1.73 LC1 methoxy-biphenyl-3-yl)-3-oxazol-2-yl-propionic acid 136 3-(2′-Acetyl-5-fluoro- A3 A 2.03 354.181.6 LC1 biphenyl-3-yl)-3-oxazol-2- yl-propionic acid 1373-(2′-Cyano-5-fluoro- A3 A 2.03 337.13 1.6 LC1biphenyl-3-yl)-3-oxazol-2- yl-propionic acid 138 3-(5-Fluoro-3′- A3 A2.28 396.16 1.86 LC1 trifluoromethoxy-biphenyl- 3-yl)-3-oxazol-2-yl-propionic acid 139 3-(3-Fluoro-5-pyridin-4-yl- A3 A 8.65 343.17 1.25 LC1phenyl)-3-(5-methyl- thiazol-2-yl)-propionic acid; compound withtrifluoro-acetic acid 140 3-Oxazol-2-yl-3-(5,2′,6′- A3 A 348.18 1.7 LC1trifluoro-biphenyl-3-yl)- propionic acid 141 3-(3-Fluoro-5-pyridin-4-yl-A3 A 313.17 0.99 LC1 phenyl)-3-oxazol-2-yl- propionic acid; compoundwith trifluoro-acetic acid 142 3-(3-Fluoro-5-pyridin-3-yl- A3 A 313.181.13 LC1 phenyl)-3-oxazol-2-yl- propionic acid; compound withtrifluoro-acetic acid 143 3-[3-Fluoro-5-(3-fluoro- A3 A 331.14 1.45 LC1pyridin-4-yl)-phenyl]-3- oxazol-2-yl-propionic acid 1443-(2′-Dimethylcarbamoyl- A3 A 383.15 1.49 LC1 5-fluoro-biphenyl-3-yl)-3-oxazol-2-yl-propionic acid 145 3-(2′-Acetyl-biphenyl-3-yl)- C1 A 1.72351.21 1.5 LC1 3-(5-methyl- [1,3,4]oxadiazol-2-yl)- propionic acid 1463-(2′-Cyano-biphenyl-3- C1 A 4.74 334.18 1.5 LC1 yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)- propionic acid 147 3-(5-Methyl- C1 A 6.71 310.170.88 LC1 [1,3,4]oxadiazol-2-yl)-3-(3- pyridin-3-yl-phenyl)- propionicacid 148 3-(5-Methyl- C1 A 20.6 310.17 0.74 LC1[1,3,4]oxadiazol-2-yl)-3-(3- pyridin-4-yl-phenyl)- propionic acid 1493-(2′-Carbamoyl-5-chloro- A8 A 386.17 3.16 LC3biphenyl-3-yl)-3-(5-methyl- [1,3,4]oxadiazol-2-yl)- propionic acid 1503-(2′-Carbamoyl-5-fluoro- A9 A 370.18 2.93 LC3biphenyl-3-yl)-3-(5-methyl- [1,3,4]oxadiazol-2-yl)- propionic acid 1513-(2′-Cyano-5-fluoro- biphenyl-3-yl)-3-(5-methyl- A9 A 352.18 3.73 LC3[1,3,4]oxadiazol-2-yl)- propionic acid 152 3-(3-Fluoro-5-pyridin-4-yl-A9 A 328.14 2.07 LC3 phenyl)-3-(5-methyl- [1,3,4]oxadiazol-2-yl)-propionic acid 153 3-(3-Chloro-5-pyridin-4-yl- A8 A 344.13 2.32 LC3phenyl)-3-(5-methyl- [1,3,4]oxadiazol-2-yl)- propionic acid; compoundwith trifluoro-acetic acid 154 3-(3-Fluoro-5-pyridin-3-yl- A9 A 328.142.3 LC3 phenyl)-3-(5-methyl- [1,3,4]oxadiazol-2-yl)- propionic acid 1553-(2′-Dimethylcarbamoyl- A9 A 398.26 3.22 LC3 5-fluoro-biphenyl-3-yl)-3-(5-methyl- [1,3,4]oxadiazol-2-yl)- propionic acid 1563-[5-(2,6-Difluoro-phenyl)- A10 A 346.12 1.33 LC1pyridin-3-yl]-3-(5-methyl- [1,3,4]oxadiazol-2-yl)- propionic acid 1573-[3,3′]Bipyridinyl-5-yl-3- A10 A 311.11 0.52 LC1 (5-methyl-[1,3,4]oxadiazol-2-yl)- propionic acid 158 3-[5-(2-Carbamoyl- A10 A353.16 0.8 LC1 phenyl)-pyridin-3-yl]-3-(5- methyl-[1,3,4]oxadiazol-2-yl)-propionic acid 159 3-[5-(2,6-Dimethoxy- A10 A 370.19 1.21 LC1phenyl)-pyridin-3-yl]-3-(5- methyl-[1,3,4]oxadiazol-2- yl)-propionicacid 160 3-[5-(2-Cyano-phenyl)- A10 A 335.12 1.23 LC1pyridin-3-yl]-3-(5-methyl- [1,3,4]oxadiazol-2-yl)- propionic acid 1613-[5-(5-Chloro-2-methoxy- A10 A 374.11 1.44 LC1phenyl)-pyridin-3-yl]-3-(5- methyl-[1,3,4]oxadiazol-2- yl)-propionicacid 162 3-[5-(5-Fluoro-2-methoxy- A10 A 358.13 1.32 LC1phenyl)-pyridin-3-yl]-3-(5- methyl-[1,3,4]oxadiazol-2- yl)-propionicacid 163 3-[5-(2-Acetyl-phenyl)- A10 A 352.15 1.14 LC1pyridin-3-yl]-3-(5-methyl- [1,3,4]oxadiazol-2-yl)- propionic acid 1643-(5-Methyl- A1 A 378.16 1.17 LC1 [1,3,4]oxadiazol-2-yl)-3-(3-pyridin-4-yl-5- trifluoromethyl-phenyl)- propionic acid 165 3-(5-Methyl-A1 A 378.14 1.3 LC1 [1,3,4]oxadiazol-2-yl)-3-(3- pyridin-3-yl-5-trifluoromethyl-phenyl)- propionic acid 166 3-(2′-Carbamoyl-5- A1 A420.16 1.42 LC1 trifluoromethyl-biphenyl-3- yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)- propionic acid 167 3-Biphenyl-3-yl-3-(5- C1 A0.935 309.13 1.77 LC1 methyl-[1,3,4]oxadiazol-2- yl)-propionic acid 1683-(4-Methoxy-biphenyl-3- P4 B 4.942 340.09 4.4 LC3yl)-3-thiazol-2-yl-propionic acid (1) Mass spectroscopiccharacterization; observed mass number of the ion [(M + H)⁺], unlessspecified otherwise (2) Cathepsin A inhibitory activity determined inthe pharmacological test “Cathepsin A inhibitory activity” describedbelow. (3) St. mat is the starting material.Pharmacological Testsa) Cathepsin a Inhibitory Activity

Recombinant human cathepsin A (residues 29-480, with a C-terminal 10-Histag; R&D Systems, #1049-SE) was proteolytically activated withrecombinant human cathepsin L (R&D Systems, #952-CY). Briefly, cathepsinA was incubated at 10 μg/ml with cathepsin L at 1 μg/ml in activationbuffer (25 mM 2-(morpholin-4-yl)-ethanesulfonic acid (MES), pH 6.0,containing 5 mM dithiothreitol (DTT)) for 15 min at 37° C. Cathepsin Lactivity was then stopped by the addition of the cysteine proteaseinhibitor E-64 (N-(trans-epoxysuccinyl)-L-leucine-4-guanidinobutylamide;Sigma-Aldrich, #E3132; dissolved in activation buffer/DMSO) to a finalconcentration of 10 μM.

The activated cathepsin A was diluted in assay buffer (25 mM MES, pH5.5, containing 5 mM DTT) and mixed with the test compound (dissolved inassay buffer containing (v/v) 3% DMSO) or, in the control experiments,with the vehicle in a multiple assay plate. After incubation for 15 minat room temperature, as substrate then bradykinin carrying anN-terminal® Bodipy FL(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-propionyl)label (JPT Peptide Technologies GmbH; dissolved in assay buffer) wasadded to the mixture. The final concentration of cathepsin A was 833ng/ml and the final concentration of labeled bradykinin 2 μM. Afterincubation for 15 min at room temperature the reaction was stopped bythe addition of stop buffer (130 mM2-(4-(2-hydroxy-ethyl)-piperazin-1-yl)-ethanesulfonic acid, pH 7.4,containing (v/v) 0.013%° Triton X-100, 0.13% Coating Reagent 3 (CaliperLife Sciences), 6.5% DMSO and 20 μM ebelactone B (Sigma, #E0886)).

Uncleaved substrate and product were then separated by a microfluidiccapillary electrophoresis on a LabChip® 3000 Drug Discovery System(12-Sipper-Chip; Caliper Life Sciences) and quantified by determinationof the respective peak areas. Substrate turnover was calculated bydividing product peak area by the sum of substrate and product peakareas, and the enzyme activity and the inhibitory effect of the testcompound thus quantified. From the percentage of inhibition of cathepsinA activity observed with the test compound at several concentrations,the inhibitory concentration IC₅₀, i.e. the concentration which effects50% inhibition of enzyme activity was, calculated. IC₅₀ values ofvarious example compounds are given in Table 1, wherein “A” means anIC₅₀ value of less than 0.1 μM, “B” means an IC₅₀ value between 0.1 μMand 1 μM, and “C” means an IC₅₀ value between 1 μM and 30 μM.

B) In Vivo Antihypertrophic and Renoprotective Activity

The in vivo pharmacological activity of the compounds of the inventioncan be investigated, for example, in the model of DOCA-salt sensitiverats with unilateral nephrectomy. Briefly, in this model unilateralnephrectomy of the left kidney (UNX) is performed on Sprague Dawley ratsof 150 g to 200 g of body weight. After the operation as well as at thebeginning of each of the following weeks 30 mg/kg of body weight of DOCA(desoxycorticosterone acetate) are administered to the rats bysubcutaneous injection. The nephrectomized rats treated with DOCA aresupplied with drinking water containing 1% of sodium chloride (UNX/DOCArats). The UNX/DOCA rats develop high blood pressure, endothelialdysfunction, myocardial hypertrophy and fibrosis as well as renaldysfunction. In the test group (UNX/DOCA Test) and the placebo group(UNX/DOCA Placebo), which consist of randomized UNX/DOCA rats, the ratsare treated orally by gavage in two part administrations at 6 a.m. and 6p.m. with the daily dose of the test compound (for example 10 mg/kg ofbody weight dissolved in vehicle) or with vehicle only, respectively. Ina control group (control), which consists of animals which have not beensubjected to UNX and DOCA administration, the animals receive normaldrinking water and are treated with vehicle only. After five weeks oftreatment, systolic blood pressure (SBP) and heart rate (HR) aremeasured non-invasively via the tail cuff method. For determination ofalbuminuria and creatinine, 24 h urine is collected on metabolic cages.Endothelial function is assessed in excised rings of the thoracic aortaas described previously (W. Linz et al., JRAAS (Journal of therenin-angiotensin-aldosterone system) 7 (2006), 155-161). As a measureof myocardial hypertrophy and fibrosis, heart weight, left ventricularweight and the relation of hydroxyproline and proline are determined inexcised hearts.

The invention claimed is:
 1. A compound of the formula I, in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a physiologically acceptable salt thereof, or a physiologicallyacceptable solvate of any of them,

wherein X is S or O; D is N or —C(R3)=; R is H, (C₁-C₆)-alkyl or(C₃-C₈)-cycloalkyl; R1 is H, F, Cl, CF₃, CN, CO—H, CO—(C₁-C₆)-alkyl orCO—NR20R21; wherein R20 and R21 are independently from each other H or(C₁-C₆)-alkyl; R3 is H, methyl or ethyl; R2 is H or (C₁-C₆-)-alkyl; E₁is N or —C(R4)=; E₂ is N or —C(R5)=; E₃ is N or —C(R6)=; E₄ is N or—C(R7)=; wherein none or one of E₁, E₂, E₃ or E₄ is N; R4 is H orO—(C₁-C₆)-alkyl; R5 is H, F, Cl, CF₃, (C₁-C₆)-alkyl or(C₁-C₆)-cycloalkyl; R6 is H; R7 is H; G₁ is N or —C(R8)=; G₂ is N or—C(R9)=; G₃ is N or —C(R10)=; G₄ is N or —C(R11)=; wherein none or oneof G₁, G₂, G₃ or G₄ is N; or G₃ and G₄ are —C(R10)= and —C(R11)=,wherein R10 and R11 form a 4 to 7 membered saturated carbocycle orheterocycle with one or two oxygen atoms, wherein the carbocycle orheterocycle is optionally mono- or disubstituted by halogen and or(C₁-C₃)-alkyl; R8 is H, F, Cl, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃ orOCF₃; R9 is H, F, Cl, OH, O—(C₁-C₆)-alkyl, CH₂OH, CO—NH₂, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, CF₃ or OCF₃; R10 is H, F, Cl, OH, (C₁-C₆)-alkyl, CH₂OH,CO—O—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, CN, O—(C₁-C₆)-alkyl, CF₃ or OCF₃;and R11 is H, F, Cl, CH₂OH, CO—(C₁-C₆)-alkyl, CO—N(R20R21),CO—O—(C₁-C₆)-alkyl, CN or (C₁-C₆)-alkyl; wherein R20 and R21 areindependently from each other H or (C₁-C₃)-alkyl or form together withthe nitrogen to which they are attached a 5 or 6 membered saturatedring.
 2. The compound of claim 1, in any of its stereoisomeric forms ora mixture of stereoisomeric forms in any ratio, or a physiologicallyacceptable salt thereof, or a physiologically acceptable solvate of anyof them, wherein R2 is H.
 3. The compound of claim 1, in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a physiologically acceptable salt thereof, or a physiologicallyacceptable solvate of any of them, wherein R is H, methyl or ethyl; R1is H, F, Cl, CF₃, CN, CO—H, CO-methyl, CO—NH₂ or CO—N(CH₃)₂; R2 is H; R4is H or O-methyl; R5 is H, F, Cl, CF₃, (C₁-C₆)-alkyl or cyclopropyl; R8is H, F, Cl, methyl, O-methyl, CF₃ or OCF₃; R9 is H, F, Cl, OH,O-propyl, CH₂OH, CO—NH₂, methyl, O-methyl, CF₃ or OCF₃; R10 is H, F, Cl,OH, i-propyl, t-butyl, CH₂OH, CO—O-methyl, SO₂-methyl, CN, methyl,O-methyl, CF₃ or OCF₃; and R11 is H, F, Cl, CH₂OH, CO-methyl,CO—N(methyl)₂, CO-pyrrolidin-1-yl, CO—O-methyl, CN or methyl.
 4. Thecompound of claim 1, in any of its stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof, or a physiologically acceptable solvate of any of them, whereinG₃ and G₄ are —C(R10)= and —C(R11)=, wherein R10 and R11 form a 5 or 6membered saturated carbocycle or heterocycle with one or two oxygenatoms, wherein the carbocycle or heterocycle is optionally mono ordisubstituted by halogen and or (C₁-C₃)-alkyl.
 5. The compound of claim1, having the formula I-1 or I-11

in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a physiologically acceptable salt thereof, or aphysiologically acceptable solvate of any of them, wherein G₁ is—C(R8)=; G₂ is —C(R9)=; G₃ is —C(R10)=; and G₄ is —C(R11)=.
 6. Apharmaceutical composition, comprising at least one compound of claim 1or a physiologically acceptable salt thereof or a physiologicallyacceptable solvate of any of them, and a pharmaceutically acceptablecarrier.
 7. A method for treating a disease selected from heart failure,congestive heart failure, cardiomyopathy, myocardial infarction, leftventricular dysfunction, cardiac hypertrophy, valvular heart diseases,hypertension, atherosclerosis, peripheral arterial occlusive disease,restenosis, vascular permeability disorders, edema, thrombosis,rheumatoid arthritis, osteoarthritis, renal failure, cystic fibrosis,chronic bronchitis, chronic obstructive pulmonary disease, asthma,diabetic complications, fibrotic diseases, pain, ischemia andreperfusion damage in a patient having said disease, the methodcomprising administering to said patient a compound of the formula I asclaimed in claim 1 or a physiologically acceptable salt thereof or aphysiologically acceptable solvate of any of them.
 8. A method fortreating atrial fibrillation in a patient having atrial fibrillation,the method comprising administering to said patient a compound of theformula I as claimed in claim 1 or a physiologically acceptable saltthereof or a physiologically acceptable solvate of any of them.
 9. Acompound that is:3-(3′-tert-Butyl-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(3-Bromo-phenyl)-3-(4,5-dimethyl-thiazol-2-yl)-propionic acid;3-(3′-Methyl-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(2′-Chloro-3′-methyl-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(3′-Chloro-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(3′-Chloro-2′-methyl-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(4′-Chloro-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(2′-Chloro-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(2′,3′-Dimethyl-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-Biphenyl-3-yl-3-thiazol-2-yl-propionic acid;3-(2′-Chloro-3′-fluoro-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(2′-Methyl-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(2′-Fluoro-5′-trifluoromethyl-biphenyl-3-yl)-3-thiazol-2-yl-propionicacid; 3-(4′-Fluoro-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(2′,3′-Dichloro-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-(5-Methyl-[1,3,4]oxadiazol-2-yl)-3-(3-pyridin-4-yl-phenyl)-propionicacid; 3-(2′-Fluoro-3′-methoxy-biphenyl-3-yl)-3-thiazol-2-yl-propionicacid; 3-[3-(1-Methyl-1H-indazol-3-yl)-phenyl]-3-thiazol-2-yl-propionicacid;3-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-phenyl]-3-thiazol-2-yl-propionicacid; 3-(2′-Fluoro-5′-propoxy-biphenyl-3-yl)-3-thiazol-2-yl-propionicacid; 3-(3′-Methoxy-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(2′,5′-Difluoro-4′-methoxy-biphenyl-3-yl)-3-thiazol-2-yl-propionicacid;3-[3-(6-Amino-2-fluoro-pyridin-3-yl)-phenyl]-3-thiazol-2-yl-propionicacid; 3-(3′-Ethoxy-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(4′-Methoxy-3′,5′-dimethyl-biphenyl-3-yl)-3-thiazol-2-yl-propionicacid; 3-(3′-Propoxy-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(3′-Cyanomethoxy-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-Thiazol-2-yl-3-(3′-trifluoromethoxy-biphenyl-3-yl)-propionic acid;3-(4′-Hydroxy-3′-methoxy-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(4′-Cyclopropylmethoxy-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(5′-Fluoro-3′-isobutoxy-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(4′-Cyanomethoxy-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(4′-Benzyloxy-3′-fluoro-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-Thiazol-2-yl-3-[3′-(2,2,2-trifluoro-ethoxy)-biphenyl-3-yl]-propionicacid; 3-(3′-Benzyloxy-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(4′-Isobutoxy-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(2′-Formyl-5′-methoxy-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-(3′-Benzyloxy-4′-chloro-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid;3-[3-(6-Methoxy-pyridin-3-yl)-phenyl]-3-thiazol-2-yl-propionic acid;3-[3-(2,5-Dimethyl-2H-pyrazol-3-yl)-phenyl]-3-thiazol-2-yl-propionicacid; 3-[3-(2-Chloro-pyridin-3-yl)-phenyl]-3-thiazol-2-yl-propionicacid; 3-[3-(2-Methyl-2H-pyrazol-3-yl)-phenyl]-3-thiazol-2-yl-propionicacid; 3-[3-(3-Chloro-pyridin-4-yl)-phenyl]-3-thiazol-2-yl-propionicacid; 3-(3-Pyridin-3-yl-phenyl)-3-thiazol-2-yl-propionic acid;3-[3-(6-Cyano-pyridin-3-yl)-phenyl]-3-thiazol-2-yl-propionic acid;3-[3-(2-Fluoro-pyridin-4-yl)-phenyl]-3-thiazol-2-yl-propionic acid;3-[3-(3-Fluoro-pyridin-4-yl)-phenyl]-3-thiazol-2-yl-propionic acid;3-(3-Pyridin-4-yl-phenyl)-3-thiazol-2-yl-propionic acid;3-{3-[5-(Morpholine-4-carbonyl)-pyridin-3-yl]-phenyl}-3-thiazol-2-yl-propionicacid;3-(5′-Chloro-2′-fluoro-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′-Fluoro-3′-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′,5′-Difluoro-4′-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid; 3-(2′-Fluoro-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′-Fluoro-4′-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid; 3-(2′-Acetyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid; 3-(2′-Carbamoyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-[3-(3-Fluoro-pyridin-4-yl)-phenyl]-3-(5-methyl-thiazol-2-yl)-propionicacid; 3-(5-Methyl-thiazol-2-yl)-3-(3-pyridin-3-yl-phenyl)-propionicacid;3-(5-Methyl-thiazol-2-yl)-3-{3-[5-(morpholine-4-carbonyl)-pyridin-3-yl]-phenyl}-propionicacid; 3-(5-Methyl-thiazol-2-yl)-3-(3-pyridin-4-yl-phenyl)-propionicacid;3-(3′-Chloro-2′-fluoro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′-Fluoro-4-methoxy-4′-methyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′,5′-Difluoro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5′-Fluoro-4-methoxy-2′-methyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5′-Chloro-2′-fluoro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′-Chloro-5′-fluoro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(3′-Chloro-4-methoxy-2′-methyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4-Methoxy-4′-methyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′,3′-Difluoro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(3′-Fluoro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4-Methoxy-2′,3′-dimethyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′-Fluoro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′-Fluoro-4-methoxy-3′-methyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′,4′-Difluoro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4-Methoxy-2′,4′-dimethyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4′-Chloro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′-Fluoro-4,4′-dimethoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4-Methoxy-2′-methyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4′-Chloro-2′-fluoro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4′-Fluoro-4-methoxy-2′-methyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(3′-Chloro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′-Chloro-3′-fluoro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4-Methoxy-4′-trifluoromethyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4′-Fluoro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4,3′-Dimethoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′-Fluoro-4-methoxy-5′-methyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′-Chloro-4′-fluoro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′-Chloro-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4-Methoxy-4′-trifluoromethoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4-Methoxy-3′-methyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4-Methoxy-3′-trifluoromethyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4,4′-Dimethoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4′-Cyano-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid; 3-(3‘-Cyano-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4-Methoxy-2’-trifluoromethyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(4-Methoxy-3‘-trifluoromethoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2’-Carbamoyl-4-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2-Methoxy-5-pyridin-4-yl-phenyl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2-Methoxy-5-pyridin-3-yl-phenyl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-[5-(3-Fluoro-pyridin-4-yl)-2-methoxy-phenyl]-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5-Chloro-2′,5′-difluoro-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5-Chloro-2′-fluoro-3′-methyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5,3′-Dichloro-2′-fluoro-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5-Chloro-2′-fluoro-5′-methyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′-Acetyl-5-chloro-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5-Chloro-2′-fluoro-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5-Chloro-2′,6′-difluoro-4′-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5-Chloro-2′,3′-difluoro-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′-Carbamoyl-5-chloro-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5-Chloro-3′-trifluoromethoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(3-Chloro-5-pyridin-4-yl-phenyl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5-Chloro-2′-fluoro-4′-methoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5-Chloro-2′-cyano-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(3-Chloro-5-pyridin-3-yl-phenyl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5-Chloro-2′-dimethylcarbamoyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-[3-Chloro-5-(3-fluoro-pyridin-4-yl)-phenyl]-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5,2′-Difluoro-5′-methyl-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid; 3-(5,2′-Difluoro-3′-methyl-biphenyl-3-yl)-3-oxazol-2-yl-propionicacid;3-(5-Methyl-thiazol-2-yl)-3-(5,2′,5′-trifluoro-biphenyl-3-yl)-propionicacid;3-(2′-Acetyl-5-fluoro-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(5,2′-Difluoro-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid; 3-(5,2′-Difluoro-5′-methyl-biphenyl-3-yl)-3-oxazol-2-yl-propionicacid;3-(5-Fluoro-3′-trifluoromethoxy-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid; 3-(5,2′-Difluoro-4′-methyl-biphenyl-3-yl)-3-oxazol-2-yl-propionicacid;3-Oxazol-2-yl-3-(5,2′,6′-trifluoro-4′-methoxy-biphenyl-3-yl)-propionicacid;3-(2′-Carbamoyl-5-fluoro-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(3-Fluoro-5-pyridin-3-yl-phenyl)-3-(5-methyl-thiazol-2-yl)-propionicacid; 3-Oxazol-2-yl-3-(5,2′,3′-trifluoro-biphenyl-3-yl)-propionic acid;3-Oxazol-2-yl-3-(5,2′,5′-trifluoro-biphenyl-3-yl)-propionic acid;3-(2′-Cyano-5-fluoro-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid;3-(2′-Dimethylcarbamoyl-5-fluoro-biphenyl-3-yl)-3-(5-methyl-thiazol-2-yl)-propionicacid; 3-(5,2′-Difluoro-biphenyl-3-yl)-3-oxazol-2-yl-propionic acid;3-(2′-Carbamoyl-5-fluoro-biphenyl-3-yl)-3-oxazol-2-yl-propionic acid;3-(5,2′-Difluoro-4′-methoxy-biphenyl-3-yl)-3-oxazol-2-yl-propionic acid;3-(2′-Acetyl-5-fluoro-biphenyl-3-yl)-3-oxazol-2-yl-propionic acid;3-(2′-Cyano-5-fluoro-biphenyl-3-yl)-3-oxazol-2-yl-propionic acid;3-(5-Fluoro-3′-trifluoromethoxy-biphenyl-3-yl)-3-oxazol-2-yl-propionicacid;3-(3-Fluoro-5-pyridin-4-yl-phenyl)-3-(5-methyl-thiazol-2-yl)-propionicacid; 3-Oxazol-2-yl-3-(5,2′,6′-trifluoro-biphenyl-3-yl)-propionic acid;3-(3-Fluoro-5-pyridin-4-yl-phenyl)-3-oxazol-2-yl-propionic acid;3-(3-Fluoro-5-pyridin-3-yl-phenyl)-3-oxazol-2-yl-propionic acid;3-[3-Fluoro-5-(3-fluoro-pyridin-4-yl)-phenyl]-3-oxazol-2-yl-propionicacid;3-(2′-Dimethylcarbamoyl-5-fluoro-biphenyl-3-yl)-3-oxazol-2-yl-propionicacid;3-(2′-Acetyl-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-(2′-Cyano-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-(5-Methyl-[1,3,4]oxadiazol-2-yl)-3-(3-pyridin-3-yl-phenyl)-propionicacid;3-(5-Methyl-[1,3,4]oxadiazol-2-yl)-3-(3-pyridin-4-yl-phenyl)-propionicacid;3-(2′-Carbamoyl-5-chloro-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-(2′-Carbamoyl-5-fluoro-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-(2′-Cyano-5-fluoro-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-(3-Fluoro-5-pyridin-4-yl-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-(3-Chloro-5-pyridin-4-yl-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-(3-Fluoro-5-pyridin-3-yl-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-(2′-Dimethylcarbamoyl-5-fluoro-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-[5-(2,6-Difluoro-phenyl)-pyridin-3-yl]-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-[3,3′]Bipyridinyl-5-yl-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-[5-(2-Carbamoyl-phenyl)-pyridin-3-yl]-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-[5-(2-Cyano-phenyl)-pyridin-3-yl]-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-[5-(2-Acetyl-phenyl)-pyridin-3-yl]-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid;3-(5-Methyl-[1,3,4]oxadiazol-2-yl)-3-(3-pyridin-4-yl-5-trifluoromethyl-phenyl)-propionicacid;3-(5-Methyl-[1,3,4]oxadiazol-2-yl)-3-(3-pyridin-3-yl-5-trifluoromethyl-phenyl)-propionicacid;3-(2′-Carbamoyl-5-trifluoromethyl-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionicacid; 3-Biphenyl-3-yl-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid;or 3-(4-Methoxy-biphenyl-3-yl)-3-thiazol-2-yl-propionic acid; in any ofits stereoisomeric forms or a mixture of stereoisomeric forms in anyratio, or a physiologically acceptable salt thereof, or aphysiologically acceptable solvate of any of them.
 10. The compound ofclaim 2, in any of its stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof, or a physiologically acceptable solvate of any of them, whereinG₃ and G₄ are —C(R10)= and —C(R11)=, wherein R10 and R11 form a 5 or 6membered saturated carbocycle or heterocycle with one or two oxygenatoms, wherein the carbocycle or heterocycle is optionally mono ordisubstituted by halogen and or (C₁-C₃)-alkyl.
 11. The compound of claim2, having the formula I-1 or I-11

in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a physiologically acceptable salt thereof, or aphysiologically acceptable solvate of any of them, wherein G₁ is—C(R8)=; G₂ is —C(R9)=; G₃ is —C(R10)=; and G₄ is —C(R11)=.
 12. Thecompound of claim 3, having the formula I-1 or I-11

in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a physiologically acceptable salt thereof, or aphysiologically acceptable solvate of any of them, wherein G₁ is—C(R8)=; G₂ is —C(R9)=; G₃ is —C(R10)=; and G₄ is —C(R11)=.
 13. A methodfor treating a disease selected from heart failure, myocardialinfarction, left ventricular dysfunction, cardiac hypertrophy,hypertension and atherosclerosis, the method comprising administering toa patient having said disease a compound of the formula I as claimed inclaim 1 or a physiologically acceptable salt thereof or aphysiologically acceptable solvate of any of them.
 14. A method fortreating a disease selected from cystic fibrosis, chronic bronchitis,chronic obstructive pulmonary disease and asthma, the method comprisingadministering to a patient having said disease a compound of the formulaI as claimed in claim 1 or a physiologically acceptable salt thereof ora physiologically acceptable solvate of any of them.
 15. A method fortreating renal failure, the method comprising administering to a patientexperiencing renal failure a compound of the formula I as claimed inclaim 1 or a physiologically acceptable salt thereof or aphysiologically acceptable solvate of any of them.
 16. A method fortreating neuropathic pain, the method comprising administering to apatient a compound of the formula I as claimed in claim 1 or aphysiologically acceptable salt thereof or a physiologically acceptablesolvate of any of them.
 17. A method for diuresis, the method comprisingadministering to a patient in need of diuresis a compound of the formulaI as claimed in claim 1 or a physiologically acceptable salt thereof ora physiologically acceptable solvate of any of them as a stand-alonetreatment or in combination with established diuretics.